Pyridine derivatives useful as glucokinase activators

ABSTRACT

Novel heterocyclic compounds of the formula I 
     
       
         
         
             
             
         
       
     
     in which R 1 , R 2 , R 3 , R 4  and D have the meanings indicated in claim  1 , are activators of glucokinase and can be used for the prevention and/or treatment of Diabetes Typ 1 and 2, obesity, neuropathy and/or nephropathy.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to compounds that are useful in thetreatment and/or prevention of diseases mediated by deficient levels ofglucokinase activity, such as diabetes mellitus, and methods ofpreparing such compounds. Also provided are methods of treating diseasesand disorders characterized by underactivation of glucokinase activityor which can be treated by activating glucokinase, comprisingadministering an effective amount of a compound of this invention.

The identification of small compounds which specifically activate,regulate and/or modulate signal transduction of glucokinase is thereforedesirable and an aim of the present invention. Moreover, aim of thisinvention was the preparation of new compounds for the prevention and/ortreatment of Diabetes Type 1 and 2, obesity, neuropathy and/ornephropathy.

Surprisingly we have found that heteroaryl amino pyridines activatesglucokinase; therefore, these compounds are especially suitable for theprevention and treatment of Diabetes Type 1 and 2, obesity, neuropathyand/or nephropathy. It has been found that the compounds according tothe invention and salts thereof have very valuable pharmacologicalproperties while being well tolerated.

In particular, they exhibit glucokinase activating effects.

The present invention therefore relates to compounds according to theinvention as medicaments and/or medicament active ingredients in thetreatment and/or prophylaxis of the said diseases and to the use ofcompounds according to the invention for the preparation of apharmaceutical for the treatment and/or prophylaxis of the said diseasesand also to a process for the treatment of the said diseases whichcomprises the administration of one or more compounds according to theinvention to a patient in need of such an administration.

The host or patient may belong to any mammal species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, where they provide a model forthe treatment of a human disease.

Diabetes mellitus (DM) is a progressive disease often associated withobesity characterized by insulin deficiency and insulin resistance orboth. The fasting and post-prandial blood glucose is elevated, exposingthe patient to acute and chronic complications (micro- andmacro-vascular) leading to blindness, kidney failure, heart disease,stroke and amputations. Improving glycemic control has been demonstratedto lower the risk of these complications. Owing to the progressivenature of the disease, an evolving treatment strategy is necessary tomaintain glycemic control. There are two forms of diabetes mellitus:type 1, or juvenile diabetes or insulin-dependent diabetes mellitus(IDDM), and type 2, or adult-onset diabetes or non insulin-dependentdiabetes mellitus (NIDDM). Type 1 diabetes patients have an absoluteinsulin insufficiency due to the immunological destruction of pancreaticβ cells that synthesize and secrete insulin. Type 2 diabetes is morecomplex in etiology and is characterized by a relative insulindeficiency, reduced insulin action, and insulin resistance. Early-onsetNIDDM or maturity-onset diabetes of the young (MODY) shares manyfeatures of the most common form of NIDDM whose onset occurs in themidlife (Rotter et al 1990). A clear mode of inheritance (autosomaldominant) has been observed for MODY. At least, 3 distinct mutationshave been identified in MODY families (Bell et al. 1996). The importanceof glucokinase (GK) in glucose homeostasis has been demonstrated by theassociation of GK mutants with diabetes mellitus in humans (MODY-2) andby alteration in glucose metabolism in transgenic mice and geneknock-out mice (Froguel et al. 2003; Bali et al. 1995, Postic et al.1999).

GK, also known as hexokinase IV or D, is one of four hexokinase isozymesthat metabolize glucose to glucose 6-phosphate [Wilson, 2004]. GK isknown to be expressed in neural/neuroendocrine cells, hepatocytes andpancreatic cells and plays a central role in whole body homeostasis[Matschinsky et al. 1996; 2004]. GK plays an important role as a glucosesensor for controlling plasma glucose homeostasis by enhancing insulinsecretion from pancreatic β-cells and glucose metabolism in the liverbut also by increasing GLP1 secretion from L-Cells. β-cells,glucose-sensing in the arcuate (ARC) hypothalamic nucleus may depend onGK to detect a rise in glucose and facilitate glucose-induced-insulinsecretion. The multiple mechanisms of action of suggest that GKactivators will exert their biological effects in diabetic and obesepatients by improving the overall body glucose awareness which providesrational expectations that enhancement of GK activity would be a noveltherapeutic strategy for metabolic disorders. It is anticipated that GKactivators will restore appropriated pancreatic hormones and incretinsecretion coupled with a suppression of hepatic glucose productionwithout inducing severe hypoglycemia.

PRIOR ART

Other aminopyridine derivatives are disclosed as glucokinase activatorsin WO 2007/053345 A1, WO 2007/117381 and WO 20071089512 A1.

Other compounds with heterocyclic residues are disclosed in:US2006019967, WO2002050071, WO2004060305, WO2004103959, US2006019967,WO2007010273, WO2003013523, WO9618616, WO9618617, WO2006078621,WO200230358, WO2003027085, WO9616650, WO200196307, WO2006028958.

Following patent applications (not for GK) disclose other heterocycliccompounds WO2007023382, WO2005021529, WO200117995, US2005227989,US2004157845, WO2006101740, JP07285962, WO2007016228.

BIBLIOGRAPHY

-   Wilson J E: The hexokinase gene family. In Glucokinase and Glycemic    Disease: From Basics to Novel Therapeutics. Front Diabetes. Vol. 16.-   Matschinsky F M, Magnuson M A, Eds. Basel, Karger, 2004-   Matschinsky, F. M. Diabetes 1996, 45, 223-41.-   Matschinsky F. M.; Magnuson M. A. eds. Glucokinase and Glycemic    Disease: From Basics to Novel Therapeutics. Basel:Karger, 2004-   Rotter et al. Diabetes mellitus (1990): Theory and practice Rifkin    and Porte (Eds) NY, 378-413-   Bell et al 1996-   Froguel et al. 2003-   Bali et al. 1995-   Postic et al. 1999

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R¹, R²,-   R³, R⁴ each, independently of one another, denote H, A, Hal,    [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹²,    S(O)_(n)R¹², NR¹⁰R¹¹, NO₂, CN, COOR¹⁰, CONR¹⁰R¹¹, NR¹⁰COR¹¹,    NR¹⁰CONR¹⁰R¹¹, NR¹⁰SO_(n)R¹¹, COR¹⁰, SO₃H, SO_(n)NR¹⁰R¹¹,    O-Alk-NR¹⁰R¹¹, O-Alk-O-Alk-NR¹⁰R¹¹, O-Alk-O—R¹²,    O[C(R¹²)₂]_(m)CONR¹⁰R¹¹, O-Alk-NR¹⁰COR¹¹, O[C(R¹²)₂]_(m)Het,    O[C(R¹²)₂]_(m)Ar, S(O)_(n)[C(R¹²)₂]_(m)Het or    S(O)_(n)[C(R¹²)₂]_(m)Ar,-   D denotes

-   R⁵, R⁶,-   R⁷, R⁸ each, independently of one another, denote H, A,    [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het, [C(R¹²)₂]_(m)OCOA,    [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², S(O)_(n)R¹², NR¹⁰R¹¹, CN, COOR¹⁰,    CONR¹⁰R¹¹, NR¹⁰COR¹¹, NR¹⁰CONR¹⁰R¹¹, NR¹⁰SO_(n)R¹¹, COR¹⁰, SO₃H,    SO_(n)NR¹⁰R¹¹, O-Alk-NR¹⁰R¹¹, O[C(R¹²)₂]_(m)CONR¹⁰R¹¹,    O-Alk-NR¹⁰COR¹¹, O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar,    S(O)_(n)[C(R¹²)₂]_(m)Het or S(O)_(n)[C(R¹²)₂]_(m)Ar,-   R⁹ denotes H, A, S(O)_(n)[C(R¹²)₂]_(m)R¹⁰, CONR¹⁰R¹¹, COR¹⁰,    SO_(n)NR¹⁰R¹¹, [C(R¹²)₂]_(m)Ar or [C(R¹²)₂]_(m)Het,-   R¹⁰, R¹¹ each, independently of one another, denote H, A, Ar or Het,-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    one or two non-adjacent CH₂ groups may be replaced by O, S, SO, SO₂,    NH, NA′, NAr, NHet and/or by —CH═CH— groups and/or in addition 1-7H    atoms may be replaced by F, Cl, Br, ═S, ═NR¹² and/or ═O    -   or    -   denotes cycloalkyl having 3-7 C atoms, which is unsubstituted or        mono-, di- or trisubstituted by ═O, F, Cl, OH, OA′, OAr′, OHet′,        SO_(n)A′, SO_(n)Ar′, SO_(n)Het′, NH₂, NHA′, NA′₂, NHAr′ and/or        NHHet′,-   A′ denotes unbranched or branched alkyl having 1-6 C atoms in which    1-7H atoms may be replaced by F and/or Cl,-   Alk denotes unbranched or branched alkylene having 1, 2, 3 or 4 C    atoms,-   Ar denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A,    Hal, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het′, O[C(R¹²)₂]_(m)R¹²,    S(O)_(n)R¹², NH₂, NHA′, NA′₂, NHAr′, NHHet′, NO₂, CN, COOR¹²,    CON(R¹²)₂, NR¹²COR¹², NR¹²CON(R¹²)₂, NR¹²SO_(n)R¹², COR¹², SO₃H,    SO_(n)N(R¹²)₂, O-Alk-N(R¹²)₂, O[C(R¹²)₂]_(m)CON(R¹²)₂,    O-Alk-NR¹²COR¹², O[C(R¹²)₂]_(m)Het′, O[C(R¹²)₂]_(m)Ar′,    S(O)_(n)[C(R¹²)₂]_(m)Het′ and/or S(O)_(n)[C(R¹²)₂]_(m)Ar′,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be mono-,    di- or trisubstituted by Hal, A, [C(R¹² ₂]_(m)Ar′,    [C(R¹²)₂]_(m)Het′, O[C(R¹² ₂]_(m)Ar, O[C(R¹²)₂]_(m)Het′,    [C(R¹²)₂]_(m)cycloalkyl, [C(R¹²)₂]_(m)OR¹², [C(R¹²)₂]_(m)N(R¹²)₂,    NO₂, CN, [C(R¹²)₂]_(m)COOR¹², O[C(R¹²)₂]_(m)COOR¹²,    [C(R¹²)₂]_(m)CON(R¹²)₂, [C(R¹²)₂]_(m)CONR¹²N(R¹²)₂,    O[C(R¹²)₂]_(m)CON(R¹²)₂, O[C(R¹²)₂]_(m)CONR¹²N(R¹²)₂,    [C(R¹²)₂]_(m)NR¹²COA, NR¹²CON(R¹²)₂, [C(R¹²)₂]_(m)NR¹²SO₂A, COR¹²,    SO₂N(R¹²)₂, S(O)_(m)A, ═S, ═NR² and/or ═O (carbonyl oxygen),-   Ar′ denotes phenyl, naphthyl or biphenyl, each of which is    unsubstituted or mono-, di- or trisubstituted by Hal, A, OR¹²,    N(R¹²)₂, NO₂, CN, COOR¹², CON(R¹²)₂, NR¹²COA, NR¹²CON(R¹²)₂,    NR¹²SO₂A, COR¹², SO₂N(R¹²)₂, S(O)_(n)A, [C(R¹²)₂]_(m)COOR¹² and/or    O[C(R¹²)₂]_(m)COOR¹²,-   Het′ denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be mono-,    di- or trisubstituted by Hal, A, OR¹², N(R¹²)₂, NO₂, CN, COOR¹²,    CON(R¹²)₂, NR¹²COA, NR¹²SO₂A, COR¹², SO₂N(R¹²)₂, S(O)_(n)A, ═S,    ═NR¹² and/or ═O (carbonyl oxygen),-   R¹² denotes H or unbranched or branched alkyl having 1, 2, 3, 4, 5    or 6 C atoms    -   or    -   denotes cycloalkyl having 3-7 C atoms,-   Hal denotes F, Cl, Br or I,-   m denotes 0, 1, 2, 3 or 4,-   n denotes 0, 1 or 2,    with the proviso that if D denotes thiazole then R¹ is not equal    OCH₂Ar or OCH₂Het,    and pharmaceutically usable salts and stereoisomers thereof,    including mixtures thereof in all ratios.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and pharmaceutically usable salts and stereoisomers thereof,characterised in that

-   a) wherein    -   D denotes

characterised in thata compound of the formula II

-   -   in which    -   R¹, R², R³ and R⁴ have the meanings indicated in claim 1,        is reacted with a compound of the formula III

-   -   in which    -   L denotes Cl, Br, I or a free or reactively functionally        modified OH group and    -   R⁵ and R⁶ have the meanings indicated in claim 1,        or

-   b) wherein    -   D denotes

characterised in thata compound of the formula IV

-   -   in which    -   R¹, R², R³, R⁴ and Hal have the meanings indicated in claim 1,        is reacted with a compound of the formula V

D-NH₂  V

-   -   in which D denotes

-   -   and R⁷, R⁸ and R⁹ have the meanings indicated in claim 1,        or

-   c) in a compound of the formula I, a radical R⁶ is converted into    another radical R⁶ by    -   i) converting a halogen group to an aromatic heterocycle;    -   ii) converting an ester to an alcohol group        and/or        a base or acid of the formula I is converted into one of its        salts.

Compounds of the formula I also mean their pharmaceutically usablederivatives and their solvates.

The invention also relates to the stereoisomers (E, Z isomers) and thehydrates and solvates of these compounds. Solvates of the compounds aretaken to mean adductions of inert solvent molecules onto the compoundswhich form owing to their mutual attractive force. Solvates are, forexample, mono- or dihydrates or alcoholates.

Pharmaceutically usable derivatives is taken to mean, for example, thesalts of the compounds according to the invention and also so-calledprodrug compounds.

Prodrug derivatives is taken to mean compounds of the formula I whichhave been modified, with, for example, alkyl or acyl groups, sugars oroligopeptides and which are rapidly cleaved in the organism to form theactive compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as is described, for example, in Int. J.Pharm. 115, 61-67 (1995).

The expression “effective amount” means the amount of a medicament orpharmaceutical active ingredient which causes a biological or medicalresponse which is sought or aimed at, for example by a researcher orphysician, in a tissue, system, animal or human.

In addition, the expression “therapeutically effective amount” means anamount which, compared with a corresponding subject who has not receivedthis amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or prevention of side effectsor also the reduction in the progress of a disease, condition, disorderor side effects or also the reduction in the progress of a disease,condition or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

For all radicals which occur more than once, their meanings areindependent of one another.

Above and below, the radicals and parameters R¹, R², R³, R⁴ and D havethe meanings indicated for the formula I, unless expressly indicatedotherwise.

A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

Moreover, A preferably denotes unbranched or branched alkyl having 1-10C atoms, in which one or two non-adjacent CH₂ groups may be replaced byO, S and/or NH and/or in addition 1-7H atoms may be replaced by F, Cland/or Br, or denotes cycloalkyl having 3-7 C atoms, which isunsubstituted or monosubstituted by ═O.

Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

Alk preferably denotes CH₂ or CH₂CH₂.

R¹ preferably denotes H, O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar,O-Alk-NR¹⁰R¹¹, O-Alk-O-Alk-NR¹⁰R¹¹, O-Alk-O—R¹² or[C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹²;

R¹ more preferably denotes H, O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar,O-Alk-NR¹⁰R¹¹, O-Alk-O-Alk-NR¹⁰R¹¹, O-Alk-O—R¹² or[C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², wherein

-   R¹⁰, R¹¹ each, independently of one another, denote H or A,-   R¹² denotes H or unbranched or branched alkyl having 1, 2, 3, 4, 5    or 6 C atoms or    -   denotes cycloalkyl having 3-7 C atoms, unsubstituted or        monosubstituted by ═O,-   Alk denotes unbranched or branched alkylene having 1, 2, 3 or 4 C    atoms,-   Het denotes a monocyclic saturated heterocycle having 1 to 2 N,    and/or S atoms, which may be unsubstituted or mono- or disubstituted    by A and/or ═O (carbonyl oxygen),-   m denotes 0, 1 or 2.

R² preferably denotes H.

R³ preferably denotes Hal, [C(R¹²)₂]_(m)Ar,[C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar orS(O)_(n)[C(R¹²)₂]_(m)Ar.

R³ more preferably denotes Hal, [C(R¹²)₂]_(m)Ar,[C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar orS(O)_(n)[C(R¹²)₂]_(m)Ar,

wherein

-   R¹² denotes H or unbranched or branched alkyl having 1, 2, 3, 4, 5    or 6 C atoms,-   Ar denotes phenyl, which is unsubstituted or monosubstituted by    O[C(R¹²)₂]_(m)R¹², S(O)_(n)R¹² or SO_(n)N(R¹²)₂,-   Het denotes a monocyclic aromatic heterocycle having 1 to 2 N, O    and/or S atoms,-   m denotes 0, 1 or 2,-   n denotes 0, 1 or 2.

R³ particularly preferably denotes F, Cl, Br, phenoxy, benzyloxy,phenylsulfanyl, phenylsulfinyl, phenylsulfonyl, aminosulfonyl-phenoxy,pyridyloxy, carbamoyl-pyridyl-methoxy, methoxybenzyl, methoxy, ethoxy,propoxy or 2-methoxy-ethoxy; most preferably R³ denotes Br, phenoxy,benzyloxy, methoxy, ethoxy, propoxy or 2-methoxy-ethoxy.

R⁴ preferably denotes H.

R⁶ preferably denotes H.

R⁶ preferably denotes H, A, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het,[C(R¹²)₂]_(m)OCOA, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹² or COOR¹².

R⁶ particularly preferably denotes H, A, [C(R¹²)₂]_(m)Het,[C(R¹²)₂]_(m)OCOA, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹² or COOR¹²,

wherein

-   R¹² denotes H or unbranched or branched alkyl having 1, 2, 3, 4, 5    or 6 C atoms,-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    one or two non-adjacent CH₂ groups may be replaced by O, S and/or NH    and/or in addition 1-7H atoms may be replaced by F, Cl and/or Br,-   Het denotes a monocyclic aromatic heterocycle having 1 to 2 N, O    and/or S atoms,-   denotes 0, 1 or 2.-   R⁷ preferably denotes H.-   R⁸ preferably denotes H.-   R⁹ preferably denotes H, A or [C(R¹²)₂]_(m)Het.-   R⁹ more preferably denotes H, A or [C(R¹²)₂]_(m)Het, wherein-   R¹² denotes H,-   A denotes unbranched or branched alkyl having 1-6 C atoms,-   Het denotes a monocyclic aromatic heterocycle having 1 to 2 N, O    and/or S atoms,-   denotes 0, 1 or 2.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert.-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-ureidophenyl, o-, m- or p-formylphenyl,o-, m- or p-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- orp-carboxyphenyl, o-, m- or p-carboxymethylphenyl, o-, m- orp-carboxymethoxyphenyl, further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl,3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-,2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar preferably denotes, for example, phenyl which is unsubstituted ormonosubstituted by O[C(R¹²)₂]_(m)S(O)_(n)R¹² or SO_(n)N(R¹²)₂

Ar particularly preferably denotes, for example, phenyl which isunsubstituted or monosubstituted by OCH₃, SO₂CH₃ or SO₂NH₂.

Ar′ preferably denotes, for example, phenyl which is unsubstituted ormono-, di- or trisubstituted by Hal, A, OH, OA, SO₂A, COOA or CN, veryparticularly preferably phenyl which is unsubstituted or mono-, di- ortrisubstituted by Hal and/or A.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2,4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 1-, 3-, 4-, 5-,6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl,3-, 4-, 5-, 6-, 7- or 8-innolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl,5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl,further preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals can also be partially or fully hydrogenated.

Het can thus also denote, for example, 2,3-dihydro-2-, -3-, -4- or-5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or-3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, further preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het preferably denotes a monocyclic saturated, unsaturated or aromaticheterocycle having 1 to 4 N, O and/or S atoms, which may beunsubstituted or mono- or disubstituted by A, [C(R¹²)₂]_(m)CON(R¹²)₂and/or ═O (carbonyl oxygen).

Het particularly preferably denotes furyl, thienyl, pyrrolyl,imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, pyrrolidinyl,piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,tetrahydrothienyl or piperazinyl, each of which is unsubstituted ormono- or disubstituted by A, [C(R¹²)₂]_(m)CON(R¹²)₂ and/or ═O (carbonyloxygen).

Het′ preferably denotes a monocyclic saturated, unsaturated or aromaticheterocycle having 1 to 2 N and/or O atoms, which may be unsubstitutedor mono-, di- or trisubstituted by A, Hal, OH and/or OA.

Het′ particularly preferably denotes a monocyclic saturated heterocyclehaving 1 to 2 N and/or O atoms, which may be unsubstituted or mono- ordisubstituted by A.

In a further embodiment, Het′ very particularly denotes pyrrolidinyl,piperidinyl, morpholinyl or piperazinyl.

In a further embodiment, Het′ particularly preferably denotes furyl,thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl,thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl orpiperazinyl, each of which is unsubstituted or mono-, di- ortrisubstituted by A, Hal, OH and/or OA.

Mono- or bicyclic saturated, unsaturated or aromatic heterocycledenotes, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or3-pyrrolyl, 1-, 2,4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-,-3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6- or7-indazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or2,1,3-benzoxadiazol-5-yl, furthermore 2,3-dihydro-2-, -3-, -4- or-5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or-3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, 2,3-methylenedioxyphenyl,3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl,3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl,2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl oralso 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to It, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R¹, R²,    -   R³, R⁴ each, independently of one another, denote H, A, Hal,        [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het,        [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², O[C(R¹²)₂]_(m)Het,        O[C(R¹²)₂]_(m)Ar, S(O)_(n)[C(R¹²)₂]_(m)Het, O-Alk-NR¹⁰R¹¹,        O-Alk-O-Alk-NR¹⁰R¹¹, O-Alk-O—R¹² or S(O)_(n)[C(R¹²)₂]_(m)Ar;-   in Ib R¹ denotes H, O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar,    O-Alk-NR¹⁰R¹¹, O-Alk-O-Alk-NR¹⁰R¹¹, O-Alk-O—R¹² or    [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹²;-   in Ic R² denotes H;-   in Id R³ denotes Hal, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het,    [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar,    S(O)_(n)[C(R¹²)₂]_(m)Het or S(O)_(n)[C(R¹²)₂]_(m)Ar;-   in Ie R³ denotes Hal, [C(R¹²)₂]_(m)Ar,    [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar    or S(O)_(n)[C(R¹²)₂]_(m)Ar;-   in If R⁴ denotes H;-   in Ig R⁵, R⁶,    -   R⁷, R⁸ each, independently of one another, denote H, A,        [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het, [C(R¹²)₂]_(m)OCOA,        [C(R )₂]_(m)O[C(R¹²)₂]_(m)R¹² or COOR¹²;-   in Ih R⁵ denotes H;-   in Ii R⁶ denotes H, A, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het,    [C(R¹²)₂]_(m)OCOA, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹² or COOR¹²;-   in Ij R⁷ denotes H;-   in Ik R⁸ denotes H;-   in Il R⁹ denotes H, A or [C(R¹²)₂]_(m)Het;-   in Im R¹⁰, R¹¹ each, independently of one another, denote H or A;-   in In A denotes unbranched or branched alkyl having 1-10 C atoms, in    which one or two non-adjacent CH₂ groups may be replaced by O, S    and/or NH and/or in addition 1-7H atoms may be replaced by F, Cl    and/or Br,    -   or    -   denotes cycloalkyl having 3-7 C atoms, which is unsubstituted or        monosubstituted by ═O;-   in Io Ar denotes phenyl, which is unsubstituted or monosubstituted    by O[C(R¹²)₂]_(m)R¹², S(O)_(n)R¹² or SO_(n)N(R¹²)₂;-   in Ip Het denotes a monocyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono- or disubstituted by A, [C(R¹²)₂]_(m)CON(R¹²)₂    and/or ═O (carbonyl oxygen);-   in Iq Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyridyl,    pyrimidinyl, pyrazolyl, thiazolyl, pyrrolidinyl, piperidinyl,    morpholinyl, tetrahydropyranyl, terahydrofuranyl, tetrahydrothienyl    or piperazinyl, each of which is unsubstituted or mono- or    disubstituted by A, [C(R¹²)₂]_(m)CON(R¹²)₂ and/or ═O (carbonyl    oxygen);-   in Ir R¹, R²,    -   R³, R⁴ each, independently of one another, denote H, A, Hal,        [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het,        [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², O-Alk-NR¹⁰R¹¹,        O-Alk-O-Alk-NR¹⁰R¹¹, O-Alk-O—R¹², O[C(R¹²)₂]_(m)Het,        O[C(R¹²)₂]_(m)Ar, S(O)_(n)[C(R¹²)₂]_(m)Het or        S(O)_(n)[C(R¹²)₂]_(m)Ar,    -   D denotes

-   -   R⁵, R⁶,    -   R⁷, R⁸ each, independently of one another, denote H, A,        [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het, [C(R¹²)₂]_(m)OCOA,        [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹² or COOR¹²,    -   R⁹ denotes H, A or [C(R¹²)₂]_(m)Het,    -   R¹⁰, R¹¹ each, independently of one another, denote H or A,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which one or two non-adjacent CH₂ groups may be replaced by O, S        and/or NH and/or in addition 1-7H atoms may be replaced by F, Cl        and/or Br,        -   or        -   denotes cycloalkyl having 3-7 C atoms, which is            unsubstituted or monosubstituted by ═O,    -   Alk denotes unbranched or branched alkylene having 1, 2, 3 or 4        C atoms,    -   Ar denotes phenyl, which is unsubstituted or monosubstituted by        O[C(R¹²)₂]_(m)R¹², S(O)_(n)R¹² or SO_(n)N(R¹²)₂,    -   Het denotes a monocyclic saturated, unsaturated or aromatic        heterocycle having 1 to 4 N, O and/or S atoms, which may be        unsubstituted or mono- or disubstituted by A,    -   R¹² denotes H or unbranched or branched alkyl having 1, 2, 3, 4,        5 or 6 C atoms        -   or        -   denotes cycloalkyl having 3-7 C atoms, unsubstituted or            monosubstituted by ═O,    -   Hal denotes F, Cl, Br or I,    -   m denotes 0, 1, 2, 3 or 4,    -   n denotes 0, 1 or 2,

-   in Is R¹ denotes H, O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar,    O-Alk-NR¹⁰R¹¹, O-Alk-O-Alk-NR¹⁰R¹¹, O-Alk-O—R¹² or    [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹²,    -   R² denotes H,    -   R³ denotes Hal, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹²,        O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar or S(O)_(n)[C(R¹²)₂]_(m)Ar,    -   R⁴ denotes H,    -   D denotes

-   -   R⁵ denotes H,    -   R⁶ denotes H, A, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het,        [C(R¹²)₂]_(m)OCOA, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹² or COOR¹²,    -   R⁷ denotes H,    -   R⁸ denotes H,    -   R⁹ denotes H, A or [C(R¹²)₂]_(m)Het,    -   R¹⁰, R¹¹ each, independently of one another, denote H or A,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which one or two non-adjacent CH₂ groups may be replaced by O, S        and/or NH and/or in addition 1-7H atoms may be replaced by F, Cl        and/or Br,        -   or        -   denotes cycloalkyl having 3-7 C atoms, which is            unsubstituted or monosubstituted by ═O,    -   Alk denotes unbranched or branched alkylene having 1, 2, 3 or 4        C atoms,    -   Ar denotes phenyl, which is unsubstituted or monosubstituted by        O[C(R¹²)₂]_(m)R¹², S(O)_(n)R¹² or SO_(n)N(R¹²)₂,    -   Het denotes a monocyclic saturated, unsaturated or aromatic        heterocycle having 1 to 4 N, O and/or S atoms, which may be        unsubstituted or mono- or disubstituted by A,    -   R¹² denotes H or unbranched or branched alkyl having 1, 2, 3, 4,        5 or 6 C atoms        -   or        -   denotes cycloalkyl having 3-7 C atoms, unsubstituted or            monosubstituted by ═O,    -   Hal denotes F, Cl, Br or I,    -   m denotes 0, 1, 2, 3 or 4,    -   n denotes 0, 1 or 2;

-   in It R¹² denotes H;    with the proviso that if D denotes thiazole then R¹ is not equal    OCH₂Ar or OCH₂Het;    and pharmaceutically usable salts and stereoisomers thereof,    including mixtures thereof in all ratios.

The compounds according to the invention and also the starting materialsfor their preparation are, in addition, prepared by methods known perse, as described in the literature (for example in the standard works,such as Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se, which are notmentioned here in greater detail.

If desired, the starting materials can also be formed in situ so thatthey are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds according to theinvention.

The starting compounds are generally known. If they are novel, however,they can be prepared by methods known per se.

Compounds of the formula I,

whereinD denotes

can preferably be obtained by reacting a compound of the formula II witha compound of the formula III.

In the compounds of the formula III L is Cl, Br, OH or a reactiveesterified OH group. If L is a reactive esterified OH group, this ispreferably alkylsulfonyloxy having 1-6 C atoms (preferablymethylsulfonyloxy) or arylsulfonyloxy having 6-10 C atoms (preferablyphenyl- or p-tolylsulfonyloxy, and also 2-naphthalenesulfonyloxy).

The reaction is carried out by methods which are known to the personskilled in the art.

The reaction is generally carried out in an inert solvent.

The starting substances of the formulae II and III are known in somecases. If they are not known, they can be prepared by methods known perse.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 110°, in particular between about 20°and about 100°.

Compounds of the formula I,

whereinD denotes

can preferably be obtained by reacting a compound of the formula IV witha compound of the formula V.

The reaction preferably is carried out in presence of a catalyst such astris(dibenzylidene-aceton)-dipalladium and BINAP(2,2′-bis(diphenylphosphino)-1,1-binaphthyl). BINAP is the ligand to thecatalyst. Other preferred ligands are tri-(o-tolyl)-phosphine,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl,2-(di-tert.-butylphosphino)biphenyl orchloro(di-2-norbornylphosphino)(2-dimethylaminoferrocen-1-yl)palladium(II).

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an alkali or alkaline-earth metal hydroxide, carbonateor bicarbonate or another salt of a weak acid of the alkali oralkaline-earth metals, preferably of potassium, sodium, calcium orcaesium. The addition of an organic base, such as triethylamine,dimethylaniline, pyridine or quinoline may also be favourable.

Particularly preferred is sodium-tert.-butylate orpotassium-tert.-butylate.

The starting substances of the formulae IV and V are known in somecases. If they are not known, they can be prepared by methods known perse.

In detail, the reaction of the compounds of the formulae IV and V iscarried out in the presence or absence of an inert solvent and attemperatures as described above.

It is furthermore possible to convert a radical R⁶ in a compound of theformula I into another radical R⁶ by, for example, converting a halogengroup to an aromatic heterocycle or converting an ester to an alcoholgroup.

Other radicals can be converted by reducing nitro groups (for example byhydrogenation on Raney nickel or Pd/carbon in an inert solvent, such asmethanol or ethanol) to amino groups or hydrolysing cyano groups to COOHgroups.

Furthermore, free amino groups can be acylated in a conventional mannerusing an acid chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide, advantageously in an inert solvent, such asdichloromethane or THF, and/or in the presence of a base, such astriethylamine or pyridine, at temperatures between −60 and +30°. Estergroups can be saponified, for example, using NaOH or KOH in water,water/THF or water/dioxane at temperatures between 0 and 100°.Carboxylic acids can be converted, for example using thionyl chloride,into the corresponding carboxylic acid chlorides, and the latter can beconverted into carboxamides. Elimination of water therefrom in a knownmanner gives carbonitriles.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtent-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Compounds of the formula I according to the invention may be chiralowing to their molecular structure and may accordingly occur in variousenantiomeric forms. They can therefore exist in racemic or in opticallyactive form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

The invention furthermore relates to the use of the compounds and/orphysiologically acceptable salts thereof for the preparation of amedicament (pharmaceutical composition), in particular by non-chemicalmethods. They can be converted into a suitable dosage form here togetherwith at least one solid, liquid and/or semi-liquid excipient or adjuvantand, if desired, in combination with one or more further activeingredients.

The invention furthermore relates to medicaments comprising at least onecompound according to the invention and/or pharmaceutically usable saltsand stereoisomers thereof, including mixtures thereof in all ratios, andoptionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the disease conditiontreated, the method of administration and the age, weight and conditionof the patient, or pharmaceutical formulations can be administered inthe form of dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbent, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape which arebroken up to form granules. The granules can be lubricated by additionof stearic acid, a stearate salt, talc or mineral oil in order toprevent sticking to the tablet casting moulds. The lubricated mixture isthen pressed to give tablets. The compounds according to the inventioncan also be combined with a free-flowing inert excipient and thenpressed directly to give tablets without carrying out the granulation ordry-pressing steps. A transparent or opaque protective layer consistingof a shellac sealing layer, a layer of sugar or polymer material and agloss layer of wax may be present. Dyes can be added to these coatingsin order to be able to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compounds. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds according to the invention and salts, solvates andphysiologically functional derivatives thereof can also be administeredin the form of liposome delivery systems, such as, for example, smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from various phospholipids, such as,for example, cholesterol, stearylamine or phosphatidylcholines.

The compounds according to the invention and the salts, solvates andphysiologically functional derivatives thereof can also be deliveredusing monoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds can also be coupled to solublepolymers as targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with therecipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the presentinvention depends on a number of factors, including, for example, theage and weight of the human or animal, the precise disease conditionwhich requires treatment, and its severity, the nature of theformulation and the method of administration, and is ultimatelydetermined by the treating doctor or vet. However, an effective amountof a compound according to the invention is generally in the range from0.1 to 100 mg/kg of body weight of the recipient (mammal) per day andparticularly typically in the range from 1 to 10 mg/kg of body weightper day. Thus, the actual amount per day for an adult mammal weighing 70kg is usually between 70 and 700 mg, where this amount can beadministered as an individual dose per day or usually in a series ofpart-doses (such as, for example, two, three, four, five or six) perday, so that the total daily dose is the same. An effective amount of asalt or solvate or of a physiologically functional derivative thereofcan be determined as the fraction of the effective amount of thecompound according to the invention per se. It can be assumed thatsimilar doses are suitable for the treatment of other conditionsmentioned above.

The invention furthermore relates to medicaments comprising at least onecompound according to the invention and/or pharmaceutically usable saltsand stereoisomers thereof, including mixtures thereof in all ratios, andat least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound according to the invention    and/or pharmaceutically usable salts and stereoisomers thereof,    including mixtures thereof in all ratios,    -   and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound according tothe invention and/or pharmaceutically usable salts and stereoisomersthereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, in particular for humans, in the treatment of Diabetes Typ1 and 2, obesity, neuropathy and/or nephropathy.

The invention thus relates to the use of compounds according to claim 1and to pharmaceutically usable salts and stereoisomers, includingmixtures thereof in all ratios, for the preparation of a medicament forthe treatment of Diabetes Typ 1 and 2, obesity, neuropathy and/ornephropathy.

The compounds of the present invention can be used as prophylactics ortherapeutic agents for treating diseases or disorders mediated bydeficient levels of glucokinase activity or which can be treated byactivating glucokinase including, but not limited to, diabetes mellitus,impaired glucose tolerance, IFG (impaired fasting glucose) and IFG(impaired fasting glycemia), as well as other diseases and disorderssuch as those discussed below.

Furthermore, the compounds of the present invention can be also used toprevent the progression of the borderline type, impaired glucosetolerance, IFG (impaired fasting glucose) or IFG (impaired fastingglycemia) to diabetes mellitus.

The compounds of the present invention can be also used as prophylacticsor therapeutic agents of diabetic complications such as, but not limitedto, neuropathy, nephropathy, retinopathy, cataract, macroangiopathy,osteopenia, diabetic hyperosmolar coma), infectious diseases (e.g.,respiratory infection, urinary tract infection, gastrointestinal tractinfection, dermal soft tissue infection, lower limb infection etc.),diabetic gangrene, xerostomia, decreased sense of hearing,cerebrovascular disease, peripheral circulatory disturbance, etc.

The compounds of the present invention can be also used as prophylacticsor therapeutic agents in the treatment of diseases and disorders suchas, but not limited to, obesity, metabolic syndrome (syndrome X),hyperinsulinemia, hyperinsulinemia-induced sensory disorder,dyslipoproteinemia (abnormal lipoproteins in the blood) includingdiabetic dyslipidemia, hyperlipidemia, hyperlipoproteinemia (excess oflipoproteins in the blood) including type I, II-a(hypercholesterolemia), II-b, III, IV (hypertriglyceridemia) and V(hypertriglyceridemia), low HDL levels, high LDL levels, atherosclerosisand its sequelae, vascular restenosis, neurodegenerative disease,depression, CNS disorders, liver steatosis, osteoporosis, hypertension,renal diseases (e.g., diabetic nephropathy, glomerular nephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,terminal renal disorder etc.), myocardiac infarction, angina pectoris,and cerebrovascular disease (e.g., cerebral infarction, cerebralapoplexy).

The compounds of the present invention can be also used as prophylacticsor therapeutic agents in the treatment of diseases and disorders suchas, but not limited to, osteoporosis, fatty liver, hypertension, insulinresistant syndrome, inflammatory diseases (e.g., chronic rheumatoidarthritis, spondylitis deformans, osteoarthritis, lumbago, gout,postoperative or traumatic inflammation, remission of swelling,neuralgia, pharyngolaryngitis, cystitis, hepatitis (includingnon-alcoholic steatohepatitis), pneumonia, inflammatory colitis,ulcerative colitis), pancreatitis, visceral obesity syndrome, cachexia(e.g., carcinomatous eachexia, tuberculous cachexia, diabetic cachexia,hemopathic cachexia, endocrinopathic cachexia, infectious cachexia,cachexia induced by acquired immunodeficiency syndrome), polycysticovary syndrome, muscular dystrophy, tumor (e.g., leukemia, breastcancer, prostate cancer, skin cancer etc.), irritable bowel syndrome,acute or chronic diarrhea, spondylitis deformans, osteoarthritis,remission of swelling, neuralgia, pharyngolaryngitis, cystitis, SIDS,and the like.

The compounds of the present invention can be used in combination withone or more additional drugs such as described below. The dose of thesecond drug can be appropriately selected based on a clinically employeddose. The proportion of the compound of formula I and the second drugcan be appropriately determined according to the administration subject,the administration route, the target disease, the clinical condition,the combination, and other factors. In cases where the administrationsubject is a human, for instance, the second drug may be used in anamount of 0.01 to 100 parts by weight per part by weight of the compoundof formula I.

The second compound of the pharmaceutical combination formulation ordosing regimen preferably has complementary activities to the compoundof formula I such that they do not adversely affect each other. Suchdrugs are suitably present in combination in amounts that are effectivefor the purpose intended. Accordingly, another aspect of the presentinvention provides a composition comprising a compound of formula I, ora solvate, metabolite, or pharmaceutically acceptable salt or prodrugthereof, in combination with a second drug, such as described herein.

The compound of formula I and the additional pharmaceutically activeagent(s) may be administered together in a unitary pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially in any order. Such sequentialadministration may be close in time or remote in time. The amounts ofthe compound of formula I and the second agent(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect.

The combination therapy may provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e., serially, whereas incombination therapy, effective dosages of two or more active ingredientsare administered together.

The compounds of the present invention can be used, for example incombination with additional drug(s) such as a therapeutic agent fordiabetes mellitus, and/or a therapeutic agent for diabeticcomplications, as defined above.

Examples of known therapeutic agents for diabetes mellitus which can beused in combination with a compound of formula I include insulinpreparations (e.g., animal insulin preparations extracted from thebovine or swine pancreas; human insulin preparations synthesized by agenetic engineering technique using Escherichia coli or a yeast), afragment of insulin or derivatives thereof (e.g., INS-i), agents forimproving insulin resistance (e.g., pioglitazone hydrochloride,troglitazone, rosiglitazone or its maleate, GI-262570, JTT-50 1,MCC-555, YM-440, KRP-297, CS-Oil, FK-614), alpha-glucosidase inhibitors(e.g., voglibose, acarbose, miglitol, emiglitate), biguanides (e.g.,phenformin, metformin, buformin), insulin secretagogues [sulfonylureas(e.g., tolbutamide, glibenclamide, gliclazide, chiorpropamide,tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide,glybuzole), repaglinide, nateglinide, mitiglinide or its calcium salthydrate, GLP-1J, dipeptidylpeptidase IV inhibitors (e.g., NVP-DPP-278,PT-100), beta-3 agonists CL-3 16243, SR-58611-A, UL-TG-307, SB-226552,AJ-9677, BMS-196085, AZ-40140, etc.), amylin agonists (e.g.,pramlintide), phosphotyrosine phosphatase inhibitors (e.g., vanadicacid), gluconeogenesis inhibitors (e.g., glycogen phosphorylaseinhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists),SGLT (sodium-glucose cotransporter) inhibitors (e.g., T-1095), and thelike.

Examples of known therapeutic agents for diabetic complications includealdose reductase inhibitors (e.g., tolrestat, epairestat, zenarestat,zopobestat, minairestat, fidarestat (SNK-860), CT-i 12), neurotrophicfactors (e.g., NGF, NT-3, BDNF), neurotrophic factor productionsecretion promoters, PKC inhibitors (e.g., LY-333531), AGE inhibitors(e.g., ALT946, pimagedine, pyratoxathine, N-phenacylthiazolium bromide(ALT766), EXO-226), active oxygen scavengers (e.g., thioctic acid), andcerebral vasodilators (e.g., tiapuride, mexiletine).

The compounds of the present invention can also be used, for example incombination with antihyperlipidemic agents. Epidemiological evidence hasfirmly established hyperlipidemia as a primary risk factor in causingcardiovascular disease (CVD) due to atherosclerosis. In recent years,emphasis has been placed on lowering plasma cholesterol levels, and lowdensity lipoprotein cholesterol in particular, as an essential step inprevention of CVD.

Cardiovascular disease is especially prevalent among diabetic subjects,at least in part because of the existence of multiple independent riskfactors in this population. Successful treatment of hyperlipidemia inthe general population, and in diabetic subjects in particular, istherefore of exceptional medical importance. Examples ofantihyperlipidemic agents include statin compounds which are cholesterolsynthesis inhibitors (e.g., cerivastatin, pravastatin, simvastatin,lovastatin, atorvastatin, fluvastatin, itavastatin or their salts,etc.), squalene synthase inhibitors or fibrate compounds (e.g.,bezafibrate; clofibrate, simfibrate, clinofibrate) having a triglyceridelowering action and the like.

The compounds of the present invention can also be used, for example incombination with hypotensive agents. Hypertension has been associatedwith elevated blood insulin levels, a condition known ashyperinsulinemia. Insulin, a peptide hormone whose primary actions areto promote glucose utilization, protein synthesis and the formation andstorage of neutral lipids, also acts to promote vascular cell growth andincrease renal sodium retention, among other things. These latterfunctions can be accomplished without affecting glucose levels and areknown causes of hypertension. Peripheral vasculature growth, forexample, can cause constriction of peripheral capillaries, while sodiumretention increases blood volume. Thus, the lowering of insulin levelsin hyperinsulinemics can prevent abnormal vascular growth and renalsodium retention caused by high insulin levels and thereby alleviateshypertension. Examples of hypotensive agents include angiotensinconverting enzyme inhibitors (e.g., captopril, enalapril, delapril),angiotensin II antagonists (e.g., candesartan cilexetil, losartan,eprosartan, valsantan, termisartan, irbesartan, tasosartan), calciumantagonists (e.g., manidipine, nifedipine, nicardipine, amlodipine,efonidipine), and clonidine.

The compounds of the present invention can be used in combination withantiobesity agents. The term “obesity” implies an excess of adiposetissue. Obesity is a well-known risk factor for the development of manyvery common diseases such as diabetes, atherosclerosis, andhypertension. To some extent appetite is controlled by discrete areas inthe hypothalamus: a feeding centre in the ventrolateral nucleus of thehypothalamus (VLH) and a satiety centre in the ventromedial hypothalamus(VMH). The cerebral cortex receives positive signals from the feedingcenter that stimulate eating, and the satiety center modulates thisprocess by sending inhibitory impulses to the feeding center. Severalregulatory processes may influence these hypothalamic centers. Thesatiety center may be activated by the increases in plasma glucoseand/or insulin that follow a meal. Examples of antiobesity agentsinclude antiobesity drugs acting on the central nervous system (e.g.,dexfenfluramine, fenfluramine, phentermine, sibutramine, anfepramon,dexamphetamine, mazindol, phenylpropanolamine, clobenzorex), pancreaticlipase inhibitors (e.g. orlistat), beta-3 agonists (e.g., CL-3 16243,SR-5861 1-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140),anorectic peptides (e.g., leptin, CNTF (Ciliary Neurotrophic Factor) andcholecystokinin agonists (e.g. lintitript, FPL-1 5849).

Assays Glucokinase Activation Screening Assay

GK activity (human or rat enzyme) is measured by an coupled enzyme assayusing pyruvate kinase (PK) and lactate dehydrogenase (LDH) as couplingenzymes. GK activity is calculated from the decline in NADH monitoredphotometrically with a microtiter plate (MTP) reader at 340 nm. Forscreening purposes, the GK assay is routinely run in a 384-MTP format,in a total volume of 33 μl/well. 10 μl of the ATP-regeneration solution(in HEPES-buffer*, pH 7.0, 6.73 U/ml pyruvate kinase, 6.8 U/ml lactatedehydrogenase) and 10 μl of the glucokinase-/glucose solution (15 μg/ml,6.6 mM glucose in HEPES-buffer*, pH 7.0; the concentration of theglucose stock-solution was 660 mM in Millipore H₂O) were mixed togetherwith 3 μl of a 10% DMSO solution (in HEPES-buffer*, pH 7.0) containing3.3-fold the amounts of the compounds to achieve final compoundconcentrations in the range between 1 nM to 30 μM (sometimes 300 μM) inthe assay solution (s. below). The solutions were mixed for 5 sec, andafter a centrifugation at 243×g for 5 min, the solutions werepreincubated for 25 min at room temperature.

The reaction was started by the addition of 10 μl of theNADH-/ATP-solution (4.29 mM NADH, 4.95 mM ATP, in HEPES-buffer*). TheMTP was shaken for 5 sec., and then, the absorbance at 340 nm wasmonitored continuously in a MTP-reader (TECAN Spectro fluor plus) forthe next 27 min (with a MTP-cycling time of 199 sec.). The finalconcentrations of the various components were as follows: 49.5 mM Hepes,pH 7.0, 1.49 mM PEP, 1.3 mM NADH, 49.5 mM KCl, 4.96 mM MgCl₂, 1.5 mMMg-ATP, 1.98 mM DTT, 2.04 U/ml pyruvate kinase, 2.06 U/mllactate-dehydrogenase, 0.91% DMSO, 0.15 μg/well glucokinase, and testcompounds in the range between 1 nM and 300 μM.

The change in the optical density (ΔOD_(340 nm)) in the presence of thecompound was expressed relative to the ΔOD_(340 nm, ctrl) of the controlincubation (in the presence of 2 mM glucose and 0.91% DMSO), taking intoaccount the optical density of the blank sample (incubation in theabsence of 2 mM glucose). For the determination of the half maximaleffective concentration (EC₅₀), the %−Ctrl-values were plotted in asemi-logarithmic graph against the conc. of the compound of interest.The data points were fitted to a sigmoid curve function(f(x)=((%−Ctrl_(max)%−Ctrl_(mm))/(1−(EC₅₀/x**^(n(Hill))))+%−Ctrl_(min)))by a non-linear regression analysis.

* Hepes-buffer (50 mM Hepes, pH 7.0, 5 mM MgCl₂, 50 mM KCl, 1.5 mM PEP,0.1% BSA). DTT was added to the Hepes-buffer from a 200× stock solution(in Millipore H₂O) freshly each day. The final concentration of DTT inthe Hepes-buffer is 2 mM.

Culture of Pancreatic INS-1 Cells

INS-1 cells were cultured in complete medium, RPMI 1640 containing 1 mMsodium pyruvate, 50 μM 2-mercaptoethanol, 2 mM glutamine, 10 mM HEPES,100 IU/mL penicillin, and 100 μg/mL streptomycin (CM), supplemented with10 mM glucose, and 10% (vol/vol) heat-inactivated fetal calf serum(FCS), as described by Asfari et al. (Endocrinology 130: 167-178, 1992).

Insulin Secretion Assay

INS-1 cells were plated and cultured in 48-well plates. After 2 days ofculture, the medium was removed and cells were cultured for 24 h with amedium change to 5 mM glucose, 1% FCS. The cells were then washed withKrebs-Ringer Bicarbonate HEPES buffer (KRBH; 135 mM NaCl; 3.6 mM KCl; 5mM NaHCO3; 0.5 mM NaH2PO4; 0.5 mM MgCl2; 1.5 mM CaCl2 and 10 mM HEPES;pH 7.4) 0.1% BSA containing 2.8 mM glucose and preincubated for 30 minat 37° C. in the same buffer. The cells were then washed twice andincubated for 1 h in KRBH 0.1% BSA containing 2.8 or 4.2 mM glucose anddifferent concentrations of the tested molecule. Insulin concentrationin the collected supernatants was measured with ELISA using rat insulinantibody (Insulin Rat Elit PLUS, cat. ref 10-1145-01).

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention.

Persons skilled in the art will recognize that the chemical reactionsdescribed may be readily adapted to prepare a number of otherglucokinase activators of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within thescope of this invention. For example, the synthesis of non-exemplifiedcompounds according to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: if necessary, water is added,the pH is adjusted, if necessary, to between 2 and 10, depending on theconstitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the product is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent: ethyl acetate/methanol 9:1.

-   Mass spectrometry (MS): EI (electron impact ionisation) M⁺    -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺ (unless indicated        otherwise)        Melting Points (mp.): melting points are determined with a BÜCHI        Melting Point B-540

LC-MS- and HPLC-conditions

The in the following examples mentioned mass data are from LC-MSmeasurement, the respective Ion (M+H⁺ or M+Na⁺) is given as m/z: HewlettPackard System of the HP 1100 series with the following characteristics:Ion source: Electrospray (positive mode); Scan: 100-1000 m/z;Fragmentation-voltage: 60 V; Gas-temperature: 300° C., DAD: 220 nm. Flowrate: 2.4 ml/Min. The used splitter reduced the flow rate after the DADfor the MS to 0.75 ml/Min.

Column: Chromolith Speed ROD RP-18e 50-4.6

Solvent: LiChrosolv-quality from the company Merck KGaA

Solvent A: H₂O (0.01% TFA) Solvent B: ACN (0.01% TFA)

Method A: In 2.8 min from 80% A to 100% B, followed by 0.2 min 100% Band 1 min 80% A;Method B: Gradient in 3 min from 95% A to 100% B, followed by 0.8 min95% A;Method C: In 2 min from 90% A to 100% B, followed, by 3 min 100% B and 1min 90% A;Method D: 1 min 100% A. In 2.5 min from 100% A to 100% B, followed by1.5 min 100% B and 1 min 100% A.

EXAMPLE 1 Preparation of(5-bromo-pyridine-2-yl)-(4-methyl-thiazole-2-yl)-amine (“A1”)

1.1 Ammoniumthiocyanat (76 mmol, 1.2 eq.) is dissolved in acetone (75ml) and benzoylchloride (1 eq.) is added dropwise. 20 min after stirringat RT, the reaction is heated to reflux. 2-Amino-5-bromopyridine (71mmol) in acetone (50 ml) is added and 30 min heated to reflux.Afterwards, the reaction solution is poured onto ice. The precipitate isfiltered and washed with water/methanol (1:1). The precipitate isdissolved in 2M NaOH (120 ml) at 80° C. and stirred 10 min at 80° C. Thesolution is poured into an HCl solution (5%) at 0° C. The pH of thesolution is adjusted to 8 with a saturated Na₂CO₃ solution. Theresulting precipitate is filtered and washed with water.(5-Bromo-pyridine-2-yl)-thiourea (“1”) is obtained after drying in vacuoat 40° C. as a pale yellow solid in a yield of 63%. HPLC (method C):1.43 min; LC-MS (method A): 1.062 min, 231.95 (MH⁺).

1.2 (5-Bromo-pyridine-2-yl)-thiourea (1 mmol) is dissolved in DMF (2 ml)and 1-Chloro-propane-2-one (1 eq.) in DMF (2 ml) is added and stirred 2h at 70° C. After cooling to RT the reaction solution is poured intowater and the resulting precipitate is filtered, washed with water anddried 16 h in vacuo at 40° C.(5-Bromo-pyridine-2-yl)-(4-methyl-thiazole-2-yl)-amine is obtained as acolourless powder in a yield of 86%; mp. 241.5-242.6° C.; HPLC (methodC): 1.55 min, 269.95 (M+H⁺); LC-MS (method A): 1.432 min; ¹H-NMR(DMSO-d₆, 400 MHz): δ [ppm] 11.314 (s, 1H), 8.363 (d, 1H, J=2.9 Hz),7.865 (dd, 1H, J=2.9 Hz, J=8.9 Hz), 7.037 (d, 1H, J=8.9 Hz), 6.578 (s,1H), 2.242 (s, 3H).

EXAMPLE 2 Preparation of(4-bromomethyl-thiazole-2-yl)-(5-bromo-pyridine-2-yl)-amine (“A2”)

(5-Bromo-pyridine-2-yl)-thiourea (2.5 mmol) is dissolved in DMF (5 ml)and 1,3-dibromacetone (1 eq.) is added and stirred 2 h at 70° C. Aftercooling to RT, the reaction solution is poured into water and theresulting precipitate is filtered, washed with water and dried 16 h invacuo at 40° C. After column chromatography (ethyl acetate/methanol)(4-bromomethyl-thiazole-2-yl)-(5-bromo-pyridine-2-yl)-amine is obtainedas a colourless powder with a yield of 16%. HPLC (method C): 1.92 min;LC-MS (method A): 1.977 min, 347.95 (M+H⁺); ¹H-NMR (DMSO-d₆, 300 MHz): δ[ppm] 11.583 (s, 1H), 8.391 (d, 1H, J=2.4 Hz), 7.902 (dd, 1H, J=2.4 Hz,J=8.9 Hz), 7.119 (s, 1H), 7.023 (d, 1H, J=8.9 Hz), 4.622 (s, 2H).

EXAMPLE 3 Preparation of(5-bromo-pyridine-2-yl)-(4-imidazole-1-ylmethyl-thiazole-2-yl)-amine(“A3”)

(4-Bromomethyl-thiazole-2-yl)-(5-bromo-pyridine-2-yl)-amine (64 μmol, 1eq.), imidazole (1 eq.), K₂CO₃ (3 eq.) and potassium iodide (0.1 eq.)are dissolved in acetonitrile (1 ml) and heated to reflux for 3 h. Theproduct is purified by column chromatography: “A3” is isolated as acolourless powder (yield 49%). HPLC (method C): 1.55 min, LC-MS (methodA): 1.062 min, 335.95 (M+H⁺).

EXAMPLE 4 Preparation of2-(5-bromo-pyridine-2-ylamino)-thiazole-4-carboxylic acid ethyl ester(“A4”)

(5-Bromo-pyridine-2-yl)-thiourea (1 mmol) is dissolved in DMF (2 ml) and3-Bromo-2-oxo-propionic acid ethyl ester (1 eq.) is added and stirred 2h at 70° C. The suspension is diluted with DMF (2 ml). After cooling toRT the reaction solution is poured into water and the resultingprecipitate is filtered, washed with water and dried 16 h in vacuo at40° C. “A4” is obtained as colourless powder in a yield of 78%; mp.299.8-300.8° C.; HPLC (method C): 2.01 min; LC-MS (method A): 2.002 min,327.95 (M+H⁺);

¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 11.868 (s, 1H), 8.421 (d, 1H, J=2.3Hz), 7.926 (dd, 1H, J=8.8 Hz, J=2.3 Hz), 7.891 (s, 1H), 6.991 (d, 1H,J=8.8 Hz), 4.265 (q, 2H, J=7.2 Hz), 1.297 (t, 3H, J=7.2 Hz).

EXAMPLE 5 Preparation of acetic acid 2-(5-bromo-pyridine-2-ylamino)-thiazole-4-ylmethyl ester (“A5”)

(5-Bromo-pyridine-2-yl)-thiourea (1 mmol) is dissolved in DMF (2 ml) andacetic acid 3-chloro-2-oxo-propyl ester (1 eq.) is added and stirred 2 hat 70° C. After cooling to RT the reaction solution is poured into waterand the resulting precipitate is filtered, washed with water and dried16 h in vacuo at 40° C. “A5” is obtained as colourless powder in a yieldof 82%; mp. 200.9-201.6° C.; HPLC (method C): 1.80 min; LC-MS (methodA): 1.800 min, 327.95 (M+H⁺); ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 11.516(s, 1H), 8.391 (d, 1H, J=2.4 Hz), 7.892 (dd, 1H, J=8.9 Hz, J=2.4 Hz),7.020 (d, 1H, J=8.9 Hz), 6.998 (s, 1H), 5.015 (s, 2H), 2.062 (s, 3H).

EXAMPLE 6 Preparation of[2-(5-bromo-pyridine-2-ylamino)-thiazole-4-yl]-methanol (“A6”)

Acetic acid 2-(5-bromo-pyridine-2-yl amino)-thiazole-4-ylmethyl ester(0.29 mmol) is suspended in ethanol (1 ml) and 1 M NaOH (1 ml) is added.The suspension is stirred at RT for 75 min. The precipitate is filtered,washed with water and dried 16 h in vacuo at 40° C. “A6” is obtained asa colourless powder in a yield of 56%; mp. 207.0-209.0° C.; HPLC (methodC): 1.41 min); LC-MS (method A): 1.222 min, 285.95 (M+H⁺);

¹H-NMR (DMSO-d₆, 300 MHz): δ [ppm] 11.335 (s, 1H), 8.372 (d, 1H, J=2.4Hz), 7.870 (dd, 1H, J=8.9 Hz, J=2.4 Hz), 7.041 (d, 1H, J=8.9 Hz), 6.755(s, 1H), 5.105 (s, 1H), 4.449 (s, 2H).

EXAMPLE 7 Preparation of[4-(2-amino-ethylsulfanylmethyl)-thiazole-2-yl]-(5-bromopyridine-2-yl)-amine(“A7”)

(4-Bromomethyl-thiazole-2-yl)-(5-bromo-pyridine-2-yl)-amine (177 μmol, 1eq.), 2-amino-thio ethanol (1.1 eq.) and K₂CO₃ (1.1 eq.) are dissolvedin ethanol (3 ml) and stirred for 1 h at RT. The solvent is removed invacuo and the residue is dissolved in 0.5 M HCl and extracted with ethylacetate. The water phase is adjusted to pH 12-14 with 32% NaOH andextracted with ethyl acetate. The organic layers are combined, extractedwith brine and dried over sodium sulfate. The product is purified bypreparative reversed phase column chromatography (water/acetonitrile).“A7” is obtained as a colourless powder in a yield of 21%; HPLC (methodC): 1.48 min; LC-MS (method A): 1.108 min, 344.95 (M+H⁺); ¹H-NMR(DMSO-d₆, 500 MHz): δ [ppm] 11.400 (s, 1H), 8.342 (d, 1H, J=2.4 Hz),7.855 (dd, 1H, J=8.9 Hz, J=2.4 Hz), 7.723 (s, 2H), 6.995 (d, 1H, J=8.9Hz), 6.821 (s, 1H), 3.719 (s, 2H), 2.969-2.918 (m, 2H), 2.642 (t, 2H,J=7.8 Hz).

EXAMPLE 8 Preparation of (5-phenoxy-pyridine-2-yl)-thiazole-2-yl-amine(“A8”)

8.1 Phenol (25 mmol) is dissolved in DMF (30 ml) and NaH (1.1 eq., 60%suspension in liquid paraffin) is added at 0° C.5-Bromo-2-nitro-pyridine (1.0 eq.) in DMF (20 ml) is added and stirred16 h at RT. The reaction solution is poured into water and extractedwith ethyl acetate. The combined organic layers are washed with brine,dried over MgSO₄ and the solvent is removed in vacuo.2-Nitro-5-phenoxy-pyridine is obtained after column chromatography(heptan/ethyl acetate) as a brown oil in a yield of 78%; HPLC (methodA): 1.95 min; LC-MS: 1.678 min, 217.15 (M+H⁺).

8.2 2-Nitro-5-phenoxy-pyridine (11.3 mmol) is dissolved in acetic acid(30 ml) at 35° C. After addition of water (30 ml), zinc powder (6 eq.)is added and the reaction suspension is heated to 105° C. for 2.5 h. Thereaction suspension is cooled to RT and filtrated. The filtrate ispoured into 3.5% NaOH (700 ml) and extracted with dichloromethane. Thecombined organic phases are extracted with brine, dried over MgSO₄ andthe solvent is removed in vacuo. 5-Phenoxy-pyridin-2-ylamine is obtainedas a pink powder in a yield of 90%; HPLC (method C): 1.32 min, LC-MS(method A): 0.531 min, 187.15 (M+H⁺).

8.3 5-Phenoxy-pyridine-2-ylamine (6.1 mmol) is dissolved in THF (70 ml),cooled to 0° C. and 1,1-thiocarbonyldiimidazol (1.5 eq.) is added. Thereaction solution is stirred 3 days at 0° C. 32% NH4OH (14 ml) is addedand stirred 2 h at RT. The solvent is removed in vacuo and water (100ml) is added. The precipitate is filtered, washed with water and dried16 h in vacuo at 40° C. (5-Phenoxy-pyridin-2-yl)-thiourea is obtainedafter column chromatography (heptan/ethyl acetate) as a colourlesspowder in a yield of 52%; LC-MS (method A): 1.525 min, 246.15 (M+H⁺).

8.4 (5-Phenoxy-pyridine-2-yl)-thiourea (0.3 mmol) is dissolved in DMF (1ml) and chloro-acetaldehyde (1.1 eq., 55% in water) is added and stirred2 h at 70° C. After cooling to RT the precipitate is filtered, washedwith water and dried 16 h in vacuo at 40° C.(5-Phenoxy-pyridine-2-yl)thiazole-2-yl-amine is obtained as colourlesspowder in a yield of 66%; mp. 161.4-162.4° C.; HPLC (method C): 1.69min; LC-MS (method A): 1.559 min, 270.15 (M+H⁺); ¹H-NMR (DMSO-d₆, 500MHz): δ [ppm] 11.248 (s, 1H), 8.114 (d, 1H, J=2.7 Hz), 7.523 (dd, 1H,J=9.0 Hz, J=2.7 Hz), 7.387-7.355 (m, 3H), 7.151 (d, 1H, J=9.0 Hz), 7.107(t, 1H, J=7.1 Hz), 6.997-6.967 (m, 3H).

EXAMPLE 9 Preparation of acetic acid2-(5-phenoxy-pyridine-2-ylamino)-thiazole-4-ylmethyl ester (“A9”)

(5-Phenoxy-pyridine-2-yl)-thiourea (0.86 mmol) is dissolved in DMF (1ml) and acetic acid 3-chloro-2-oxo-propyl ester (1.1 eq.) in 1 ml DMF isadded and stirred 2 h at 70° C. After cooling to RT the precipitate isfiltered, washed with water and dried 16 h in vacuo at 40° C. “A9” isobtained after column chromatography (heptan/ethyl acetate) ascolourless powder in a yield of 69%; mp. 158.5-160.5° C.; HPLC (methodC): 1.89 min; LC-MS (method A): 1.938 min, 342.15 (M+H⁺); ¹H-NMR(DMSO-d₆, 500 MHz): δ [ppm] 11.375 (s, 1H), 8.105 (d, 1H, J=2.8 Hz),7.519 (dd, 1H, J=8.9 Hz, J=2.8 Hz), 7.389-7.347 (m, 2H), 7.120-7.088 (m,2H), 6.995-6.978 (m, 2H), 6.918 (s, 1H), 5.007 (s, 2H), 2.064 (s, 3H).

EXAMPLE 10 Preparation of[2-(5-phenoxy-pyridine-2-ylamino)-thiazole-4-yl]-methanol (“A10”)

Acetic acid 2-(5-phenoxy-pyridine-2-ylamino)-thiazole-4-ylmethyl ester(0.44 mmol) is suspended in ethanol (1.5 ml) and 1 M NaOH (1.5 ml) isadded. The solution is stirred at RT for 3 h. The reaction solution isdiluted with water. The precipitate is filtered, washed with water anddried 16 h in vacuo at 40° C. “A10” is obtained as a beige powder inyield of 88%; mp. 130.0-131.0° C.; HPLC (method C): 1.64 min; LC-MS(method A): 1.430 min, 300.15 (M+H⁺); ¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm]11.221 (s, 1H), 8.102 (d, 1H, J=2.8 Hz), 7.515 (dd, 1H, J=8.9 Hz, J=2.8Hz), 7.389-7.349 (m, 2H), 7.125-7.083 (m, 2H), 6.996-6.972 (s, 2H),6.687 (s, 1H), 5.105 (t, 1H, J=5.3 Hz), 4.442 (d, 2H, J=5.3 Hz).

EXAMPLE 11 Preparation of(5-benzyloxy-pyridine-2-yl)-(ethyl-1H-pyrazole-3-yl)amine (“A11”)

11.1 2-Bromo-5-hydroxypyridine (2 mmol) is dissolved in DMF (2.5 ml) andNaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min,benzylbromide (1.1 eq.) is added and the reaction stirred 16 h at RT.The reaction solution is diluted with water and extracted with methyltert.-butyl ether. The combined organic layers are dried over Na₂SO₄ andthe solvent removed in vacuo. 5-Benzyloxy-2-bromo-pyridine is obtainedafter column chromatography (heptan/ethyl acetate) as a colourlesspowder in a yield of 64%; HPLC (method C): 2.09 min; LC-MS (method A):1.987 min, 263.95 (M+H⁺).

11.2 5-Benzyloxy-2-bromo-pyridine (0.53 mmol), sodium-tert.-butyl at(1.4 eq.), tris-(dibenzylidene-acetone)-dipalladium (0.01 eq.), BINAP(0.01 eq.) and 1-methyl-1H-pyrazole-3-amine (1.2 eq.) are filled undernitrogen in a microwave reaction vessel. Degassed Toluene (50 eq.) isadded. The reaction suspension is heated to 120° C. for 10 min. Ethylacetate is added to the reaction suspension and filtrated over celite.The solvent of the filtrate is removed in vacuo. “A11” is obtained aftercolumn chromatography (heptan/ethyl acetate) as a colourless powder in ayield of 29%; HPLC (method C): 1.60 min); LC-MS (m Method A): 1.008 min,281.15 (M+H⁺); ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 8.859 (s, 1H), 7.886(d, 1H, J=2.5 Hz), 7.449-7.429 (m, 3H), 7.400-7.370 (m, 2H), 7.342-7.308(m, 2H), 7.246 (d, 1H, J=9.0 Hz), 6.169 (d, 1H, J=2.5 Hz), 5.062 (s,2H), 3.709 (s, 3H).

EXAMPLE 12 Preparation of(5-phenylsulfanyl-pyridine-2-yl)-thiazole-2-yl-amine (“A12”)

12.1 (5-Bromo-pyridine-2-yl)-thiourea (2.5 mmol) is dissolved in DMF (5ml) and chloroacetaldehyde (1.3 eq., 55% in water) is added and stirred5 h at 70° C. After cooling to RT, the reaction solution is poured intowater and the resulting precipitate is filtered, washed with water anddried 16 h in vacuo at 40° C.(5-Bromo-pyridine-2-yl)-thiazole-2-yl-amine is obtained as a colourlesspowder in a yield of 81%; HPLC (method C): 1.51 min; LC-MS (method A):1.464 min, 255.95 (M+H⁺).

12.2 (5-Bromo-pyridine-2-yl)-thiazole-2-yl-amine (0.66 mmol) isdissolved in THF, cooled to −70° C. and methyllithium is added (1.3 eq.,5% in diethylether). After 15 min, n-butyl lithium (1.3 eq., 15% inhexan) is added at −70° C. and diphenyldisulfide (7 eq.) is added andthe reaction solution is stirred 4 hours at −70° C. A solution ofsaturated NH₄Cl is added and extracted with dichloromethane. Thecombined organic extracts are washed with brine and dried over MgSO₄.“A12” is obtained after reversed phase column chromatography(water/acetonitrile) as a colourless powder in a yield of 20%; HPLC(method C): 1.83 min; LC-MS (method A): 1.892 min, 285.95 (M+H⁺); ¹H-NMR(DMSO-d₆, 500 MHz): δ [ppm] 11.506 (s, 1H), 8.398-8.392 (m, 1H), 7.804(dd, 1H, J=2.4 Hz, J=8.6 Hz), 7.414 (d, 1H, J=3.4 Hz), 7.334-7.307 (m,2H), 7.230-7.184 (m, 3H), 7.145 (d, 1H, J=8.6 Hz), 7.061 (d, 1H, J=3.6Hz).

EXAMPLE 13 Preparation of(5-phenylsulfinyl-pyridine-2-yl)-thiazole-2-yl-amine (“A13”)

(5-Phenylsulfanyl-pyridine-2-yl)-thiazole-2-yl-amine (0.13 mmol) isdissolved in dichloromethane, cooled to 0° C. and m-chloro-perbenzoicacid (1 eq.) is added. The reaction is stirred 30 min at 0° C. and 2.5hours at RT. Sodium disulfite (50 ml) is added and extracted withdichloromethane. The combined organic layers are washed with saturatedNaHCO₃, dried over MgSO₄ and the solvent is removed in vacuo. “A13” isobtained after reversed phase column chromatography (water/acetonitrile)as a yellow powder in a yield of 44% HPLC (method C): 1.41 min; LC-MS(method A): 1.223 min, 301.95 (M+H⁺); ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm]11.657 (s, 1H), 8.634-8.628 (m, 1H), 7.853 (dd, 1H, J=2.4 Hz, J=8.9 Hz),7.722-7.703 (m, 2H), 7.583-7.507 (m, 3H), 7.425 (d, 1H, J=3.6 Hz), 7.152(d, 1H, J=8.9 Hz), 7.100 (d, 1H, J=3.6 Hz).

EXAMPLE 14 Preparation of(5-phenylsulfonyl-pyridine-2-yl)-thiazole-2-yl-amine (“A14”)

(5-Phenylsulfanyl-pyridine-2-yl)-thiazole-2-yl-amine (0.07 mmol) isdissolved in dichloromethane, cooled to 0° C. and m-chloro-perbenzoicacid (3 eq.) is added. The reaction is stirred 30 min at 0° C. and 22hours at RT. Sodium disulfite (40 ml) is added and extracted withdichloromethane. The combined organic layers are washed with saturatedNaHCO₃, dried over MgSO₄ and the solvent is removed in vacuo. “A14” isobtained after reversed phase column chromatography (water/acetonitrile)as a colourless powder in a yield of 41%; HPLC (method C): 1.63 min;LC-MS (method A): 1.537 min, 317.95 (M+H⁺); ¹H-NMR (DMSO-d₆, 400 MHz): δ[ppm] 11.907 (s, 1H), 8.837-8.829 (m, 1H), 8.146 (dd, 1H, J=2.6 Hz,J=8.9 Hz), 8.006-7.976 (m, 2H), 7.714-7.671 (m, 1H), 7.645-7.605 (m,2H), 7.456 (d, 1H, J=3.6 Hz), 7.185-7.154 (m, 2H).

EXAMPLE 15 Preparation of[3-(2-methoxy-ethoxy)-5-phenoxy-pyridine-2-yl]-thiazole-2-yl-amine(“A20”)

Step A: 5-Chloro-3-pyridinol (15.3 mmol) is dissolved in concentratedH₂SO₄ (15 ml). At 5° C. concentrated nitric acid (0.9 ml) is added. Thereaction mixture is allowed to warm to room temperature over 6 days. Thereaction solution is pored onto ice (50 ml) and diluted with water (200ml). The precipitate is filtered, washed with water and dried at 40° C.in vacuo. 5-Chloro-2-nitro-pyridine-3-ol is obtained as yellow powder;mp. 97°; LC-MS (method B): 1.35 min, 175.1 (M+H⁺).

Step B: 5-Chloro-2-nitro-pyridine-3-ol (1.15 mmol) is dissolved in DMF(2 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added andthe suspension is stirred 45 min at room temperature.1-Bromo-2-methoxy-ethane (1 eq.) is added and the reaction suspension isheated to 100° C. for 24 hours. The reaction solution is pored intowater and extracted with dichloromethane. The combined organic layersare washed with brine, dried over MgSO₄ and the solvent is removed invacuo. 5-Chloro-3-(2-methoxy-1-ethoxy)-2-nitro-pyridine is obtainedafter column chromatography as beige solid in a yield of 60%; mp.71.5-72.5°; HPLC (method C): 1.63 min; LC-MS (method A): 1.36 min,232.95 (M+H⁺).

Step C: 5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine (0.68 mmol) isdissolved in DMF (7 ml), phenol (3 eq.) and K₂CO₃ (4 eq.) is added. Thereaction mixture is heated to 100° C. in the microwave for 30 min. Thereaction solution is pored into water and extracted withmethyl-tert.-butyl ether. The combined organic layers are washed withbrine, dried over MgSO₄ and the solvent is removed in vacuo.3-(2-Methoxy-ethoxy)-2-nitro-5-phenoxy-pyridine is obtained after columnchromatography (heptane ethyl acetate) as yellow oil in a yield of 62%;HPLC (method C): 1.93 min; LC-MS (method A): 1.80 min, 291.15 (M+H⁺).

Step D: 3-(2-Methoxy-ethoxy)-2-nitro-5-phenoxy-pyridine (0.4 mmol) isdissolved in acetic acid (1.3 ml). After addition of water (1.3 ml),zinc powder (6 eq.) is added and the reaction suspension is heated to100° C. for 3 h. The reaction suspension is cooled to room temperatureand filtrated. The filtrate is pored into 3.5% NaOH (30 ml) andextracted with dichloromethane. The combined organic layers areextracted with brine, dried over MgSO₄ and the solvent is removed invacuo. 3-(2-Methoxyethoxy)-5-phenoxy-pyridine-2-ylamine is obtained asbrown oil in a yield of 76%. HPLC (method C): 1.43 min; LC-MS (methodA): 0.808 min, 261.15 (M+H⁺).

Step E: 3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-ylamine (0.3 mmol) isdissolved in THF (4 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) isadded. The reaction solution is stirred 19 hours. 32% NH₄OH (21 eq.) isadded and stirred 3 hours at room temperature. Water (50 ml) is addedand extracted with dichloromethane. The combined organic layers arewashed with brine and dried over MgSO₄. The solvent is removed in vacuo.[3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-yl]-thiourea is obtained asbrown oil in a yield of 81%; HPLC (method C): 1.85 min; LC-MS (methodA): 1.68 min, 320.15 (M+H⁺).

Step F: [3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-yl]-thiourea (0.24mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.1 eq., 55%in water) is added and stirred 3 hours at 100° C. After cooling to roomtemperature the suspension is pored into ice-water and extracted withmethyl-tert.-butyl ether. The combined organic phases are washed withbrine and dried over MgSO₄. The solvent is removed in vacuo.[3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-yl]-thiazole-2-yl-amine(“A20”) is obtained after reversed phase chromatography(water/acetonitrile 0.1% TFA) as yellow solid in a yield of 45%; mp.140.6-140.9°; HPLC (method C): 1.73 min; LC-MS (method A): 1.589 min,344.1 (M+H⁺);

¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 10.174 (s, 1H), 7.712 (d, 1H, J=2.3Hz), 7.445 (d, 1H, J=3.7 Hz), 7.397-7.365 (m, 2H), 7.334 (d, 1H, J=2.3Hz), 7.134-7.105 (m, 1H), 7.062 (d, 1H, J=3.7 Hz), 7.032-7.013 (m, 2H),4.254-4.236 (m, 2H), 3.762-3.744 lm, 2H), 3.328 (s, 3H).

EXAMPLE 16 Preparation of(3-cyclopentyloxy-5-phenoxy-pyridine-2-yl)-thiazole-2-yl-amine (“A21”)

Step A: 5-Chloro-2-nitro-pyridine-3-ol (3.4 mmol) is dissolved in DMF (2ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added andthe suspension is stirred 45 min at room temperature. Cyclopentyliodide(1 eq.) is added and the reaction suspension is heated to 100° C. for 24hours. The reaction solution is pored into water and extracted withdichloromethane. The combined organic layers are washed with brine,dried over MgSO₄ and the solvent is removed in vacuo.5-Chloro-3-cyclopentyloxy-2-nitro-pyridine is obtained after columnchromatography as yellow oil in a yield of 60%; HPLC (method C): 2.11min; LC-MS (method A): 2.07 min, 243.10 (M+H⁺).

Step B: 5-Chloro-3-cyclopentyloxy-2-nitro-pyridine (0.8 mmol) isdissolved in DMF (8 ml), phenol (3 eq.) and K₂CO₃ (4 eq.) is added. Thereaction mixture is heated to 100° C. in the microwave for 60 min. Thereaction solution is pored into water and extracted withmethyl-tert.-butyl ether. The combined organic layers are washed withbrine, dried over MgSO₄ and the solvent is removed in vacuo.3-Cyclopentyloxy-2-nitro-5-phenoxy-pyridine is obtained after columnchromatography (heptane/ethyl acetate) as yellow oil in a yield of 60%;HPLC (method C): 2.23 min; LC-MS (method A): 2.31 min, 301.15 (M+H⁺).

Step C: 3-Cyclopentyloxy-2-nitro-5-phenoxy-pyridine (0.46 mmol) isdissolved in acetic acid (1.5 ml). After addition of water (1.5 ml),zinc powder (6.2 eq.) is added and the reaction suspension is heated to100° C. for 3 h. The reaction suspension is cooled to room temperatureand filtrated. The filtrate is pored into 3.5% NaOH (30 ml) andextracted with dichloromethane. The combined organic layers are washedwith brine, dried over MgSO₄ and the solvent is removed in vacuo.3-(2-Methoxyethoxy)-5-phenoxy-pyridine-2-ylamine is obtained as brownoil in a yield of 72%; HPLC (method C): 1.43 min; LC-MS (method A):1.231 min, 271.15 (M+H⁺).

Step D: 3-Cyclopentyloxy-5-phenoxy-pyridine-2-ylamine (0.33 mmol) isdissolved in THF (5 ml) and 1,1′-thiocarbonyldiimidazol (4 eq.) isadded. The reaction solution is stirred 19 hours. 32% NH₄OH (20 eq.) isadded and stirred 3 hours at room temperature. Water (50 ml) is addedand extracted with dichloromethane. The combined organic layers arewashed with brine and dried over MgSO₄. The solvent is removed in vacuo.(3-Cyclopentyloxy-5-phenoxy-pyridine-2-yl)-thiourea is obtained as brownoil in a yield of 87%; HPLC (method C): 2.13 min; LC-MS (method A): 2.18min, 330.15 (M+H⁺).

Step E: (3-Cyclopentyloxy-5-phenoxy-pyridine-2-yl)-thiourea (0.29 mmol)is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.1 eq., 55% inwater) is added and stirred 3 h at 100° C. After cooling to roomtemperature the suspension is pored into ice-water and extracted withmethyl-ter.-butyl ether. The combined organic phases are washed withbrine and dried over MgSO₄. The solvent is removed in vacuo.(3-Cyclopentyloxy-5-phenoxy-pyridine-2-yl)-thiazole-2-yl-amine (“A21”)is obtained after reversed phase chromatography (water/acetonitrile+0.1%TFA) as yellow solid in a yield of 47%; 138.2-139.7°; HPLC (method C):2.00 min; LC-MS (method A): 2.00 min, 354.1 (M+H⁺);

¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 10.272 (s, 1H), 7.672 (d, 1H, J=2.3Hz), 7.458 (d, 1H, J=3.7 Hz), 7.409-7.377 (m, 2H), 7.211 (d, 1H, J=2.3Hz), 7.143-7.113 (m, 1H), 7.065 (d, 1H, J=3.7 Hz), 7.043-7.024 (m, 2H),4.964-4.930 (m, 1H), 1.909-1.884 (m, 4H), 1.812-1.780 (m, 2H),1.619-1.567 (m, 2H).

EXAMPLE 17 Preparation of[5-(2-methoxy-ethoxy)-pyridine-2-yl]-(1-methyl-1H-pyrazole-3-yl)-amine(“A22”)

Step A: 2-Bromo-5-hydroxypyridine (1 mmol) is dissolved in DMF (2.5 ml)and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30min 1-Bromo-2-methoxy-ethane (1.1 eq.) is added and the reactionsolution is stirred 3 days. The reaction solution is pored into waterand extracted with methyl-tert.-butyl ether. The combined organic layersare dried over MgSO₄ and the solvent is removed in vacuo.2-Bromo-5-(2-methoxyethoxy)-pyridine is obtained after columnchromatography as colorless powder in a yield of 42%; HPLC (method C):1.48 min; LC-MS (method A): 1.11 min, 231.95 (M+H⁺).

Step B: 2-Bromo-5-(2-methoxy-ethoxy)-pyridine (0.42 mmol),sodium-tert.-butylate (1.4 eq.), tris-(dibenzylidene-aceton)-dipalladium(0.1 eq.), BINAP [=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] (0.1eq.) and 1-methyl-1H-pyrazole-3-amine (1.4 eq.) are filled undernitrogen in a microwave reaction vessel. Degassed toluene (45 eq.) isadded. The reaction suspension is heated for 100 min to 120° C. and for30 min to 150° C. Ethyl acetate is added to the reaction suspension andfiltrated over celite. The solvent of the filtrate is removed in vacuo.[5-(2-Methoxy-ethoxy)-pyridine-2-yl]-(1-methyl-1H-pyrazole-3-yl)-amine(“A22”) is obtained after reversed phase column chromatography(Water/acetonitrile+0.1% TFA) as yellow oil in a yield of 35%: HPLC(method C): 1.16 min; LC-MS (method A): 0.43 min, 249.15 (M+H⁺); ¹H-NMR(DMSO-d₆, 500 MHz): δ [ppm] 10.803 (s, 1H), 7.900 (d, 1H, J=2.8 Hz),7.802 (dd, 1H, J=2.8 Hz, J=9.4 Hz), 7.739 (d, 1H, J=2.3 Hz), 7.314 (d,1H, J=9.4 Hz), 6.103 (d, 1H, J=2.3 Hz), 4.149-4.131 (m, 2H), 3.861 (s,3H), 3.688-3.670 (m, 2H), 3.323 (s, 3H).

EXAMPLE 18 Preparation of(1-methyl-1H-pyrazole-3-yl)-(5-propoxy-pyridine-2-yl)-amine (“A23”)

Step A: 2-Bromo-5-hydroxypyridine (6 mmol) is dissolved in DMF (10 ml)and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30min 1-iodopropane (1.1 eq.) is added and the reaction solution isstirred 18 hours. The reaction solution is pored into water andextracted with methyltert.-butyl ether. The combined organic layers aredried over MgSO₄ and the solvent is removed in vacuo.2-Bromo-5-propoxy-pyridine is obtained as yellow oil in a yield of 87%;HPLC (method C): 1.93 min; LC-MS (method A): 1.78 min, 215.95 (M+H⁺).

Step B: 2-Bromo-5-propoxy-pyridine (0.96 mmol), sodium-tert.-butylate(1.4 eq.), and 1-methyl-1H-pyrazole-3-amine (1.3 eq.) are dissolved indegassed dioxane (2 ml) and heated to 80° C.Chloro-(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium(II) (5.9 mg) in degassed dioxane (1 ml) is added and the reactionmixture is heated for 60 min to 150° C. in the microwave. The reactionis quenched with ethylacetate/methanol (30 ml, 9:1) and filtrated overcelite. The solvent of the filtrate is removed in vacuo.(1-Methyl-1H-pyrazole-3-yl)-(5-propoxy-pyridine-2-yl)-amine (“A23”) isobtained after reversed phase column chromatography(water/acetonitrile+0.1% TFA) as a colorless powder in a yield of 43%;HPLC (method C): 1.41 min; LC-MS (method A): 0.81 min, 233.0 (M+H⁺);¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm] 10.651 (s, 1H), 7.869 (d, 1H, J=2.9Hz), 7.747-7.710 (m, 2H), 7.299 (d, 1H, J=9.6 Hz), 6.099 (d, 1H, J=2.3Hz), 3.949 (t, 2H, J=6.4 Hz), 3.841 (s, 3H), 1.785-1.697 (m, 2H), 3.323(t, 3H, J=7.4 Hz).

EXAMPLE 19 Preparation of(5-methoxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)-amine (“A24”)

Step A: 2-Bromo-5-hydroxypyridine (5 mmol) is dissolved in DMF (10 ml)and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30min iodomethane (2 eq.) is added and the reaction solution is stirred 3days. The reaction solution is pored into water and extracted withmethyl-tert.-butyl ether. The combined organic layers are dried overMgSO₄ and the solvent is removed in vacuo. 2-Bromo-5-methoxy-pyridine isobtained as yellow oil in a yield of 79%; HPLC (method C): 1.49 min;LC-MS (method A): 1.16 min, 187.95 (M+H⁺).

Step B: 2-Bromo-5-methoxy-pyridine (0.97 mmol), sodium-tert.-butylate(1.5 eq.), and 1-methyl-1H-pyrazole-3-amine (1.3 eq.) are dissolved indegassed dioxane (2 ml) and heated to 80° C.Chloro-(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium(II) (5 mg) in degassed dioxane (1 ml) is added and the reaction isheated for 20 hours at 110° C. The reaction is quenched withethylacetate/methanol (30 ml, 9:1) and filtrated over celite. Thesolvent of the filtrate is removed in vacuo.(5-Methoxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)-amine (“A24”) isobtained after reversed phase column chromatography(water/acetonitrile+0.1% TFA) as colorless powder in a yield of 55%;HPLC (method C): 1.09 min; LC-MS (method A): 0.73 min, 205.0 (M+H⁺);

¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm] 10.951 (s, 1H), 7.889 (d, 1H, J=2.9Hz), 7.799 (dd, 1H, J=2.9 Hz, J=9.6 Hz), 7.748 (d, 1H, J=2.3 Hz), 7.328(d, 1H, J=9.6 Hz), 6.094 (d, 1H, J=2.3 Hz), 3.859 (s, 3H), 3.814 (s,3H).

EXAMPLE 20 Preparation of(5-cyclopentyloxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)amine(“A25”)

Step A: 2-Bromo-5-hydroxypyridine (3 mmol) is dissolved in DMF (10 ml)and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30min cyclopentyl iodide (2.2 eq.) is added and the reaction solution isstirred 3 days at 120° C. The reaction solution is pored into water andextracted with methyl-tert.-butyl ether. The combined organic layers aredried over MgSO₄ and the solvent is removed in vacuo.2-Bromo-5-cyclopentyloxy-pyridine is obtained after columnchromatography (heptane/ethylacetate) as yellow oil in a yield of 45%;HPLC (method C): 2.08 min; LC-MS (method A): 2.05 min, 241.95 (M+H⁺).

Step B: 2-Bromo-5-cyclopentyloxy-pyridine (0.97 mmol),sodium-tert.-butylate (1.4 eq.), and 1-methyl-1H-pyrazole-3-amine (1.2eq.) are dissolved in degassed dioxane (2 ml) and heated to 80° C.Chloro-(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium(II) (3 mg) in degassed dioxane (1 ml) is added and the reaction mixtureis heated for 1 hour at 150° C. in the microwave. The reaction isquenched with ethylacetate/methanol (30 ml, 9:1) and filtrated overcelite. The solvent of the filtrate is removed in vacuo.(5-Cyclopentyloxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)-amine(“A25”) is obtained after reversed phase column chromatography(water/acetonitrile+0.1% TEA) as a colorless powder in a yield of 29%;HPLC (method C): 1.55 min; LC-MS (method A): 0.97 min, 259.15 (M+H⁺);

¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm] 10.745 (s, 1H), 7.848 (d, 1H, J=2.9Hz), 7.739-7.709 (m, 2H), 7.282 (d, 1H, J=9.6 Hz), 6.091 (d, 1H, J=2.3Hz), 4.793-4.764 (m, 1H), 3.850 (s, 3H), 1.953-1.865 (m, 2H),1.751-1.688 (m, 4H), 1.661-1.583 (m, 2H).

EXAMPLE 21 Preparation of(5-isobutoxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)amine (“A26”)

Step A: 2-Bromo-5-hydroxypyridine (2 mmol) is dissolved in DMF (10 ml)and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30min 1-Bromo-2-methylpropane (1.1 eq.) is added and the reaction solutionis stirred 3 days at 100° C. The reaction solution is pored into waterand extracted with methyl-tert.-butyl ether. The combined organic layersare dried over MgSO₄ and the solvent is removed in vacuo.2-Bromo-5-isobutoxy-pyridine is obtained after reversed phase columnchromatography (water/acetonitrile+0.1% TFA) as a yellow oil in a yieldof 19%; HPLC (method C): 2.08 min; LC-MS (method A): 2.05 min, 241.95(M+H⁺).

Step B: 2-Bromo-5-isobutoxy-pyridine (0.38 mmol), sodium-tert.-butylate(1.4 eq.), and 1-methyl-1H-pyrazole-3-amine (1.2 eq.) are dissolved indegassed dioxane (2 ml) and heated to 80° C.Chloro-(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium(II) (3 mg) in degassed dioxane (1 ml) is added and the reaction isheated for 1 hour at 150° C. in the microwave. The reaction is quenchedwith ethylacetate methanol (30 ml, 9:1) and filtrated over celite. Thesolvent of the filtrate is removed in vacuo.(5-Isobutoxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)amine (“A26”) isobtained after reversed phase column chromatography(water/acetonitrile+0.1% TFA) as colorless powder in a yield of 33%;HPLC (method C): 1.57 min; LC-MS (method A): 0.936 min, 247.15 (M+H⁺);

¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 10.289 (s, 1H), 7.858 (d, 1H, J=2.9Hz), 7.663-7.644 (m, 2H), 7.282 (d, 1H, J=9.6 Hz), 6.107 (d, 1H, J=2.3Hz), 3.817 (s, 3H), 3.760 (d, 2H, J=6.5 Hz), 2.058-1.978 (m, 1H), 0.982(d, 6H, J=6.8 Hz).

EXAMPLE 22 Preparation of[5-(4-methanesulfonyl-phenoxy)-pyridine-2-yl]-(1-methyl-1H-pyrazol-3-yl)-amine(“A27”)

Step A: 2-Bromo-5-hydroxypyridine (2 mmol),4-fluoro-phenylmethyl-sulfone (1 eq.) and K₂CO₃ (1 eq.) are dissolved inDMSO (4 ml). The reaction solution is heated for 10 min to 180° C. inthe microwave. The reaction is diluted with dichloromethane andextracted with 1 N NaOH and brine. The organic layer is dried over MgSO₄and the solvent is removed in vacuo.2-Bromo-5-(4-methanesulfonyl-phenoxy)-pyridine is obtained after columnchromatography (heptane/ethylacetate) as a colorless powder in a yieldof 31%; HPLC (method C): 1.71 min; LC-MS (method A): 1.46 min, 327.95(M+H⁺).

Step B: 2-Bromo-5-(4-methanesulfonyl-phenoxy)-pyridine (0.47 mmol),sodium-tert.-butylate (1.4 eq.), and 1-methyl-1H-pyrazole-3-amine (1.2eq.) are dissolved in degassed dioxane (2.5 ml) and heated to 80° C.Chloro(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium(II) (5.9 mg) in degassed dioxane (1 ml) is added and the reactionmixture is heated for 1 hour at 142° C. in the microwave. The reactionis quenched with ethylacetate (30 ml) and filtrated over celite. Thesolvent of the filtrate is removed in vacuo[5-(4-Methanesulfonyl-phenoxy)-pyridine-2-yl]-(1-methyl-1H-pyrazole-3-yl)-amine(“A27”) is obtained after reversed phase column chromatography(water/acetonitrile+0.1% TFA) as orange powder in a yield of 55%; HPLC(method C): 1.57 min; LC-MS (method A): 0.787 min, 345.15 (M+H⁺);

¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 9.317 (s, 1H), 8.020 (d, 1H, J=2.9Hz), 7.883 (d, 2H, J=8.9 Hz), 7.504 (d, 1H, J=2.2 Hz), 7.470 (dd, 1H,J=2.9 Hz, J=9.0 Hz), 7.355 (d, 1H, J=9.0 Hz), 7.125 (d, 2H, J=8.9 Hz),6.268 (d, 1H, J=2.2 Hz), 3.740 (s, 3H), 3.170 (s, 3H).

EXAMPLE 23 Preparation of[3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridine-2-yl]-thiazole-2-yl-amine(“A28”)

Step A: 5-Chloro-3-pyridinol (382 mmol) is dissolved in concentratedH₂SO₄ (375 ml). At 5° C. concentrated nitric acid (25 ml) is added. Thereaction is allowed to warm to room temperature over 3 hours. Thereaction solution is pored onto ice water (5000 ml). The precipitate isfiltered, washed with water and dried over night at 40° C. in vacuo.5-Chloro-2-nitro-pyridine-3-ol is obtained as yellow powder in a yieldof 74%. Mp.: 97° C.; LC-MS (Method B): 1.35 min, 175.1 (MH⁺).

Step B: 5-Chloro-2-nitro-pyridine-3-ol (5.7 mmol) is dissolved in THF(35 ml) and triphenylphosphin (2 eq.) and 1-Methoxy-2-propanol (1 eq.)is added at 0° C. After addition of di-tert.-butylazodicarboxylate (1.5eq) in THF (10 ml), the reaction is stirred five hours at 0° C. Thesolvent is removed in vacuo.5-Chloro-3-(2-methoxy-1-methyl-ethoxy)-2-nitro-pyridine is obtainedafter column chromatography (heptan/ethylacetate) as yellow solid in ayield of 100%. HPLC (method C): 1.81 min; LC-MS (method A): 1.64 min,247.05 (MH⁺).

Step C: 5-Chloro-3-(2-methoxy-1-methyl-ethoxy)-2-nitro-pyridine (2 mmol)is dissolved in DMF (15 ml), phenol (3 eq.) and K₂CO₃ (4 eq.) is added.The reaction is heated to 100° C. in the microwave for 45 min. Thereaction solution is pored into water and extracted withmethyl-tert.-butyl ether. The combined organic layers are washed withbrine, dried over MgSO₄ and the solvent is removed in vacuo.3-(2-Methoxy-1-methyl-ethoxy)-2-nitro-5-phenoxy-pyridine is obtainedafter column chromatography (heptane/ethyl acetate) as yellow oil in ayield of 22%. HPLC (method C): 2.03 min; LC-MS (method A): 1.99 min,305.15 (MH⁺).

Step D: 3-(2-Methoxy-1-methyl-ethoxy)-2-nitro-5-phenoxy-pyridine (0.4mmol) is dissolved in acetic acid (1.5 ml). After addition of water (1.5ml), zinc powder (6 eq.) is added and the reaction suspension is heatedto 100° C. for 90 minutes. The reaction suspension is cooled to roomtemperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml)and extracted with dichloromethane. The combined organic layers areextracted with brine, dried over MgSO₄ and the solvent is removed invacuo. 3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridine-2-ylamine isobtained as yellow powder in a yield of 64%. HPLC (method C): 1.51 min,LC-MS (method A): 0.923 min, 275.15 (MH⁺).

Step E: 3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridine-2-ylamine (0.28mmol) is dissolved in THF (4 ml) and 1,1′-thiocarbonyldiimidazole (4eq.) is added. The reaction solution is stirred 22 hours. 32% NH₄OH (20eq.) is added and stirred 2 hours at room temperature. Water (60 ml) isadded and extracted with dichloromethane. The combined organic layersare washed with brine and dried over MgSO₄. The solvent is removed invacuo. [3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridin-2-yl]thiourea isobtained as yellow oil in a yield of 70%. HPLC (method C): 1.93 min;LC-MS (method A): 1.85 min, 334.15 (MH⁺).

Step F: [3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridin-2-yl]-thiourea(0.2 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.0 eq.,55% in water) is added and stirred three hours at 100° C. After coolingto room temperature the suspension is pored into ice-water and extractedwith methyl-tert.-butyl ether. The combined organic phases are washedwith brine and dried over MgSO₄. The solvent is removed in vacuo.[3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridine-2-yl]-thiazole-2-yl-amine(“A28”) is obtained after reversed phase column chromatography(acetonitrile/water+0.1% TFA) as yellow solid in a yield of 46%. HPLC(method C): 1.80 min; LC-MS (method A): 1.72 min, 358.15 (MH⁺); ¹H-NMR(DMSO-d₆, 500 MHz): δ [ppm] 7.739 (d, 1H, J=2.3 Hz), 7.477 (d, 1H, J=3.9Hz), 7.421-7.369 (m, 3H), 7.142-7.087 (m, 2H), 7.025 (d, 2H, J=8 Hz),5.408 (br, 1H), 4.737-4.696 (m, 1H), 3.639 (dd, 1H, J=6.5 Hz, J=10.6Hz), 3.505 (dd, 1H, J=3.6 Hz, J=10.6 Hz), 3.3 (S, 3H), 1.268 (D, 3H,J=6.4 Hz).

The two enantiomers can be isolated after super critical fluidchromatography (column Chiralpak AD-H with solvent system CO₂ methanol)

First from column[3-((R)-2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridin-2-yl]-thiazol-2-yl-amine(“A28a”);second from column[3-((S)-2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridin-2-yl]-thiazol-2-yl-amine(“A28b”).

EXAMPLE 24 Preparation of(3-cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiazole-2-yl-amine(“A29”)

Step A: 5-Chloro-2-nitro-pyridine-3-ol (5.7 mmol) is dissolved in THF(35 ml) and triphenylphosphin (2 eq.) and cyclopentylmethanol (1 eq.) isadded at 0° C. After addition of di-tert.-butylazodicarboxylate (1.5 eq)in THF (10 ml), the reaction is stirred five hours at 0° C. The solventis removed in vacuo. 5-Chloro-3-cyclopentylmethoxy-2-nitro-pyridine isobtained after column chromatography (heptane/ethylacetate) as yellowsolid in a yield of 74%. HPLC (method C): 2.23 min; LC-MS (method A):2.27 min, 257.05 (MH⁺).

Step B: 5-Chloro-3-cyclopentylmethoxy-2-nitro-pyridine (1.3 mmol) isdissolved in DMF (10 ml), phenol (3 eq.) and K₂CO₃ (4 eq.) is added. Thereaction is heated to 100° C. in the microwave for 45 min. The reactionsolution is pored into water and extracted with methyl-tert.-butylether. The combined organic layers are washed with brine, dried overMgSO₄ and the solvent is removed in vacuo.3-Cyclopentylmethoxy-2-nitro-5-phenoxy-pyridine is obtained after columnchromatography (heptane/ethyl acetate) as yellow oil in a yield of 94%.HPLC (method C): 2.31 min; LC-MS (method A): 2.48 min, 315.15 (MH⁺).

Step C: 3-Cyclopentylmethoxy-2-nitro-5-phenoxy-pyridine (1.2 mmol) isdissolved in acetic acid (4 ml). After addition of water (4 ml), zincpowder (6 eq.) is added and the reaction suspension is heated to 100° C.for 90 minutes. The reaction suspension is cooled to room temperatureand filtrated. The filtrate is pored into 3.5% NaOH (30 ml) andextracted with dichloromethane. The combined organic layers areextracted with brine, dried over MgSO₄ and the solvent is removed invacuo. 3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-ylamine is obtained asyellow powder in a yield of 80%. HPLC (method C): 1.83 min, LC-MS(method A): 1.486 min, 285.15 (MH⁺).

Step D: 3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-ylamine (0.97 mmol) isdissolved in THF (10 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) isadded. The reaction solution is stirred 22 hours. 32% NH₄OH (20 eq.) isadded and stirred 2 hours at room temperature. Water (250 ml) is addedand extracted with dichloromethane. The combined organic layers arewashed with brine and dried over MgSO₄. The solvent is removed in vacuo.(3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiourea is obtained asyellow solid in a yield of 70%. HPLC (method C): 2.24 min; LC-MS (methodA): 2.372 min, 344.15 (MH⁺).

Step E: (3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiourea (0.68mmol) is dissolved in DMF (3 ml) and chloro-acetaldehyde (1.0 eq., 55%in water) is added and stirred three hours at 100° C. After cooling toroom temperature the suspension is pored into ice-water and extractedwith methyl-tert.-butyl ether. The combined organic phases are washedwith brine and dried over MgSO₄. The solvent is removed in vacuo.(3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiazole-2-yl-amine(“A29”) is obtained after reversed phase column chromatography(acetonitrile/water+0.1% TFA) as yellow solid in a yield of 43%. HPLC(method C): 2.03 min; LC-MS (method A): 2.22 min, 368.15 (MH⁺); ¹H-NMR(DMSO-d₆, 500 MHz): δ [ppm] 7.705 (d, 1H, J=2.1 Hz), 7.509 (d, 1H, J=3.9Hz), 7.387 (t, 2H, J=7.9 Hz), 7.32 (d, 1H, J=2.1 Hz), 7.143-7.119 (m,2H), 7.029 (d, 2H, J=7.9 Hz), 3.992 (d, 2H, J=7.1 Hz), 3.787 (br, 1H),2A49-2.389 (m, 1H), 1.853-1.829 (m, 2H), 1.619-1.547 (m, 4H),1.371-1.320 (m, 2H).

EXAMPLE 25 Preparation of(5-benzyloxy-pyridine-2-yl)-thiazole-2-yl-amine (“A30”)

Step A: 2-Bromo-5-hydroxypyridine (3 mmol) is dissolved in DMF (2.5 ml)and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30min benzylbromide (1.1 eq.) is added and the reaction solution isstirred 24 hours. The reaction solution is pored into water andextracted with methyltert.-butyl ether. The combined organic layers aredried over Na₂SO₄ and the solvent is removed in vacuo.5-Benzyloxy-2-bromo-pyridine is obtained after column chromatography asbrown oil in a yield of 80%. HPLC (method C): 2.01 min; LC-MS (methodA): 1.97 min, 264.00 (MH⁺).

Step B: 5-Benzyloxy-2-bromo-pyridine (0.25 mmol), sodium-tert.-butylate(1.4 eq.), tris-(dibenzylideneaceton)-dipalladium (0.1 eq.),bis(2-diphenylphosphinophenyl)-ether (0.4 eq.) and 2-amino-thiazole (1.5eq.) are filled under nitrogen in a microwave reaction vessel. Degassedtoluene (45 eq.) is added. The reaction suspension is heated for 60 minto 150° C. and 60 minutes to 180° C. Ethyl acetate is added to thereaction suspension and filtrated over celite. The solvent of thefiltrate is removed in vacuo.(5-Benzyloxy-pyridine-2-yl)-thiazole-2-yl-amine (“A30”) is obtainedafter reversed phase column chromatography (water/acetonitrile+0.1% TFA)as orange oil in a yield of 34%. HPLC (method C): 1.69 min; LC-MS(method A): 1.44 min, 285.15 (MH⁺); ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm]11.108 (s, 1H), 8.072 (d, 1H, J=2.9 Hz), 7.500-7.447 (m, 3H),7.412-7.383 (m, 2H), 7.349-7.320 (m, 2H), 7.064 (d, 1H, J=9 Hz), 6.926(d, 1H, J=3.5 Hz), 5.139 (s, 2H).

EXAMPLE 25b Preparation of[3-(2-methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-yl]-thiazole-2-yl-amine(“A31”)

Step A: 5-Chloro-2-nitro-pyridine-3-ol (86 mmol) is dissolved in THF(300 ml) and triphenylphosphin (2 eq.) and ethyleneglycolmonomethylether(1 eq.) is added at 0° C. After addition ofdi-tert.-butylazodicarboxylate (2 eq) in THF (100 ml), the reaction isstirred five hours at room temperature. The solvent is removed in vacuo.5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine is obtained after columnchromatography (heptane/ethyl acetate) as yellow solid in a yield of90%. HPLC (method C): 1.59 min; LC-MS (method A): 1.47 min, 233.1 (MH⁺).

Step B: 5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine (2.6 mmol) isdissolved in DMF (12 ml), 3-hydroxypyridine (3 eq.) and K₂CO₃ (4 eq.) isadded. The reaction is heated to 120° C. in the microwave for 45 min.The solvent is removed in vacuo and dissolved in water (200 ml) andextracted with methyl-tert.-butyl ether. The combined organic layers arewashed with brine, dried over MgSO₄ and the solvent is removed in vacuo.3-(2-Methoxy-ethoxy)-2-nitro-5-(pyridine-3-yloxy)-pyridine is obtainedafter column chromatography (heptane/ethyl acetate) as yellow oil in ayield of 20%. HPLC (method C): 1.23 min; LC-MS (method A): 1.18 min,292.15 (MH⁺).

Step C: 3-(2-Methoxy-ethoxy)-2-nitro-5-(pyridine-3-yloxy)-pyridine (0.52mmol) is dissolved in acetic acid (50 eq.). After addition of water (1.5ml), zinc powder (6.3 eq.) is added and the reaction suspension isheated to 105° C. for 90 minutes. The reaction suspension is cooled toroom temperature and filtrated. The filtrate is pored into 3.5% NaOH (30ml) and extracted with dichloromethane. The combined organic layers arewashed with brine, dried over MgSO₄ and the solvent is removed in vacuo.3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-ylamine is obtainedas yellow oil in a yield of 93%. HPLC (method C): 0.44 min, LC-MS(method A): 0.46 min, 262.15 (MH⁺),

Step D: 3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-ylamine(0.48 mmol) is dissolved in THF (7 ml) and 1,1′-thiocarbonyldiimidazole(4 eq.) is added. The reaction solution is stirred 2 days. 32% NH₄OH (20eq.) is added and stirred 4 hours at room temperature. The solved isremoved in vacuo and water (150 ml) is added and extracted withdichloromethane. The combined organic layers are washed with brine anddried over MgSO₄. The solvent is removed in vacuo.[3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-yl]-thiourea isobtained as yellow solid in a yield of 69%. HPLC (method C): 1.15 min;LC-MS (method A): 0.9 min, 321.15 (MH⁺).

Step E:[3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-yl]-thiourea (0.34mmol) is dissolved in DMF (1.2 ml) and chloro-acetaldehyde (1.0 eq., 55%in water) is added and stirred 90 minutes at 120° C. After cooling toroom temperature the suspension is pored into ice-water and extractedwith methyl-tert.-butyl ether. The combined organic phases are washedwith brine and dried over MgSO₄. The solvent is removed in vacuo.[3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)pyridine-2-yl]-thiazole-2-yl-amine(“A31”) is obtained after reversed phase column chromatography(acetonitrile/water+0.1% TFA) as yellow solid in a yield of 37%. HPLC(method C): 1.17 min; LC-MS (method A): 1.07 min, 345.15 (MH⁺); ¹H-NMR(DMSO-d₆, 500 MHz): δ [ppm] 10.403 (s, 1H), 8.477 (d, 1H, J=2.7 Hz),8.398 (dd, 1H, J=1.3 Hz, J=4.6 Hz), 7.832 (d, 1H, J=2.3 Hz), 7.558-7.533(m, 1H), 7.500-7.475 (m, 2H), 7.456 (d, 1H, J=2.3 Hz), 7.116 (d, 1H,J=3.7 Hz), 4.279 (t, 2H, J=4.6 Hz), 3.771 (t, 2H, J=4.6 Hz), 3.339 (s,3H).

EXAMPLE 26 Preparation of[5-(4-methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)pyridine-2-yl]-thiazole-2-yl-amine(“A32”)

Step A: 5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine (2.6 mmol) isdissolved in DMF (12 ml), 4-(methylsulfonyl)phenol (3 eq.) and K₂CO₃ (4eq.) is added. The reaction is heated to 120° C. in the microwave for 45min. The reaction solution is pored into water and extracted withMethyltert.-butyl ether. The combined organic layers are washed withbrine, dried over MgSO₄ and the solvent is removed in vacuo.5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-2-nitro-pyridine isobtained after column chromatography (heptane/ethyl acetate) as yellowoil in a yield of 15%. HPLC (method C): 1.65 min; LC-MS (method A):1.534 min, 369.1 (MH⁺).

Step B:5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-2-nitro-pyridine(0.39 mmol) is dissolved in acetic acid (4 ml). After addition of water(1.2 ml), zinc powder (6.3 eq.) is added and the reaction suspension isheated to 105° C. for 90 minutes. The reaction suspension is cooled toroom temperature and filtrated. The filtrate is pored into 3.5% NaOH (30ml) and extracted with dichloromethane. The combined organic layers arewashed with brine, dried over MgSO₄ and the solvent is removed in vacuo.5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-ylamine isobtained as yellow oil in a yield of 96%. HPLC (method C): 1.21 min,LC-MS (method A): 0.55 min, 339.15 (MO.

Step C:5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-ylamine(0.37 mmol) is dissolved in THF (5.5 ml) and 1,1-thiocarbonyldiimidazole(4 eq.) is added. The reaction solution is stirred 3 days. 32% NH₄OH (20eq.) is added and stirred 4 hours at room temperature. Water (150 ml) isadded and extracted with dichloromethane. The combined organic layersare washed with brine and dried over MgSO₄. The solvent is removed invacuo.[5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)pyridine-2-yl]-thioureais obtained as brown oil in a yield of 75%. HPLC (method C): 1.60 min;LC-MS (method A): 1.37 min, 398.15 (MH⁺).

Step D:[5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-yl]-thiourea(0.28 mmol) is dissolved in DMF (1 ml) and chloro-acetaldehyde (1.1 eq.,55% in water) is added and stirred three hours at 100° C. After coolingto room temperature the suspension is pored into ice-water and extractedwith methyl-tert.-butyl ether. The combined organic phases are washedwith brine and dried over MgSO₄. The solvent is removed in vacuo.[5-(4-Methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-yl]-thiazole-2-yl-amine(“A32”) is obtained after reversed phase column chromatography(acetonitrile/water+0.1% TFA) as yellow solid in a yield of 22%. HPLC(method C): 1.52 min; LC-MS (method A): 1.37 min, 422.15 (MH⁺); ¹H-NMR(DMSO-d₅, 500 MHz): δ [ppm] 10.272 (s, 1H), 7.906 (d, 2H, J=8.8 Hz),7.853 (d, 1H, J=2.3 Hz), 7.462 (d, 1H, J=3.7 Hz), 7.44 (d, 1H, J=2.3Hz), 7.201 (d, 2H, J=8.8 Hz), 7.087 (d, 1H, J=3.7 Hz), 4.261 (t, 2H,J=4.5 Hz), 3.764 (t, 2H, J=4.5 Hz), 3.333 (s, 3H), 3.184 (s, 3H).

Analogously to examples 23-27 following compounds are obtained

no. name and/or structure “A33”

“A34”

“A35”

“A36”

“A37”

“A38”

“A39”

“A40”

“A41”

“A42”

“A43”

“A44”

“A45”

“A46”

“A47”

“A48”

“A49”

“A50”

“A51”

“A52”

“A53”

“A54”

“A55”

“A56”

“A57”

“A58”

“A59”

“A60”

“A61”

“A62”

“A63”

“A64”

“A65”

“A66”

“A67”

“A68”

“A69”

“A70”

“A71”

“A72”

“A73”

“A74”

“A75”

“A76”

“A77”

“A78”

“A79”

“A80”

“A81”

“A82”

“A83”

“A84”

“A85”

“A86”

“A87”

“A88”

“A89”

Analogously to preceeding examples following compounds are obtained

no. name and/or structure “A90”

HPLC (method C): 1.37 min; LCMS (method A): 1.0 min; 281.15 m/z (M +H⁺); ¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm] 10.500(br, 1H), 7.809(dd, 1H, J= 1.5 Hz, J = 5.0 Hz), 7.496(d, 1H, J = 2.3 Hz), 7.366-7.336(m, 3H),7.271-7.254(m, 2H), 7.188-7.151(m, 1H), 7.077(dd, 1H, J = 5.0 Hz, J =7.9 Hz), 5.681(d, 1H, J = 2.3 Hz), 5.147(s, 2H), 3.684(SP, 3H). “A91”

HPLC (method C): 2.59 min; LCMS (method A): 1.09 min; 259.15 m/z (M +H⁺); ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 7.844(br, 1H), 7.685 (dd, 1H, J= 1.3 Hz, J = 5.0 Hz), 7.529(d, 1H, J = 2.1 Hz), 7.173(d, 1H, J = 7.7Hz), 6.711(dd, 1H, J = 5.0 Hz, J = 7.7 Hz), 6.621(d, 1H, J = 2.1 Hz),4.909-4.880(m, 1H), 3.735(s, 3H), 1.971-1.908(m, 2H), 1.846-1.748 (m,4H), 1.629-1.599(m, 2H) “A92”

HPLC (method C): 1.29 min; LCMS (method A): 0.52 min; 249.15 m/z (M +H⁺); ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 8.046(br, 1H), 7.738 (dd, 1H, J= 1.3 Hz, J = 5.2 Hz), 7.547(d, 1H, J = 2.2 Hz), 7.261(d, 1H, J = 7.8Hz), 6.739(dd, 1H, J = 5.2 Hz, J = 7.8 Hz), 6.624(d, 1H, J = 2.2 Hz),4.199(t, 2H, J = 4.6 Hz), 3.751-3.733(m, 5H), 3.348(s, 3H). “A93”

HPLC (method C): 1.01 min; LCMS (method A): 0.69 min; 345.15 m/z (M +H⁺); ¹H-NMR (DMSO-d₆, 500 MHz): δ [ppm] 10.021(br, 1H), 7.932(DD, 1H, J= 1.5 Hz, J = 4.6 Hz), 7.675(d, 2H, J = 8.9 Hz), 7.641(d, 1H, J = 2.2Hz), 7.347(dd, 1H, J = 1.5 Hz, J = 8.0 Hz), 7.233(dd, 1H, J = 4.6 Hz, J= 8.0 Hz), 6.895(d, 2H, J = 8.9 Hz), 5.871(d, 1H, J = 2.2 Hz), 3.764(,3H), 3.118(, 3H) “A94”

HPLC (method C): 1.40 min; LCMS (method A): 0.73 min; 342.15 m/z (M +H⁺); ¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm] 11.222(br, 1H), 8.309 (dd, 1H, J= 1.3 Hz, J = 5.9 Hz), 8.254(d, 1H, J = 2.8 Hz), 8.058(t, 1H, J = 7.8Hz), 7.957-7.934(m, 2H), 7.797(dd, 1H, J = 2.8 Hz, J = 8.8 Hz), 7.530(s,1H), 7.499(d, 1H, J = 8.8 Hz), 7.245-7.223(m, 2H, J = 8.9 Hz), 7.182(t,1H, J = 6.4 Hz), 3.202(S, 3H) “A95”

HPLC (method C): 1.59 min; LCMS (method A): 1.36 min; 339.15 m/z (M +H⁺); ¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm] 9.467(d, 1H), 8.297 (br, 1H),8.269(dd, 1H, J = 1.6 Hz, J = 2.6 Hz), 8.175(d, 1H, J = 2.6 Hz),7.714(d, 1H, J = 2.4 Hz), 7.405-7.364(m, 2H), 7.139(d, 1H, J = 2.4 Hz),7.139-7.100(m, 1H), 7.045-7.021(m, 2H), 4.253-4.230(m, 2H),3.725-3.702(m, 2H), 3.315(S, 3H) “A96”

HPLC (method C): 1.72 min, LCMS (method A): 1.25 min, 338.15 m/z (MH+);1H-NMR (DMSO-d6, 500 MHz): d [ppm] 9.863(br, 1H), 8.277(d, 1H, J = 5.6Hz), 8.045(br, 2H), 7.675(d, 1H, J = 2.1 Hz), 7.492(s, 1H), 7.422(t, 2H,J = 7.7 Hz), 7.186-7.157(m, 2H), 7.083(d, 2H, J = 8.0 Hz),4.347-4.330(m, 2H), 3.752-3.735(m, 2H), 3.312(S, 3H) “A97”

HPLC (method C): 1.67 min; LCMS (method A): 1.26 min; 341.15 m/z (M +H⁺); ¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm] 8.935(br, 1H), 7.542 (d, 1H, J =2.2 Hz), 7.471(d, 1H, J = 2.2 Hz), 7.308-7.268(m, 3H), 7.047- 7.010(m,1H), 6.951-6.929(m, 2H), 6.390(d, 1H, J = 2.2 Hz), 4.196- 4.173(m, 2H),3.697(s, 3H), 3.655-3.633(s, 2H), 3.225(s, 3H) “A98”

HPLC (method C): 1.59 min; LCMS (method A): 1.09 min; 339.15 m/z (M +H⁺); ¹H-NMR (DMSO-d₆, 400 MHz): δ [ppm] 9.414(br, 1H), 8.461 (d, 2H, J =4.8 Hz), 7.703(d, 1H, J = 2.3 Hz), 7.444-7.404(m, 2H), 7.370 (d, 1H, J =2.2 Hz), 7.171(t, 1H, J = 7.3 Hz), 7.091-7.071(m, 2H), 6.905 (t, 1H, J =4.8 Hz), 4.145-4.123(m, 2H), 3.561-3.539(m, 2H), 3.187(S, 3H) “A99”

“A100”

“A101”

“A102”

“A103”

“A104”

“A105”

Pharmacological Data

TABLE 1 Glucokinase Activation Assay fold activation EC₅₀ compound nr.(human) (human) “A1” D “A2” D B “A3” D B “A4” D “A5” D B “A6” D “A7” D C“A8” D C “A9” D C “A10” E B “A11” D “A12” D C “A13” D “A14” D C “A20” EB “A21” E A “A23” D “A28” E B “A29” D A “A30” D “A31” E “A32” E B “A94”E “A95” D “A96” D “A97” E EC₅₀: 10 nM-1 μM = A 1 μM-10 μM = B >10 μM = Cfold activation: 1.2-5 μM = D 5-10 μM = E >10 μM = F

The following examples relate to pharmaceutical preparations:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient according to the inventionand 5 g of disodium hydrogenphosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised under sterile conditionsand sealed under sterile conditions. Each injection vial contains 5 mgof active ingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient according to the inventionwith 100 g of soya lecithin and 1400 g of cocoa butter is melted, pouredinto moulds and allowed to cool. Each suppository contains 20 mg ofactive ingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient according to theinvention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient according to the invention are mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient according to the invention, 4 kgof lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg ofmagnesium stearate is pressed to give tablets in a conventional mannerin such a way that each tablet contains 10 mg of active ingredient.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient according to the invention are introduced intohard gelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of an active ingredient according to the invention in60 l of bidistilled water is sterile filtered, transferred intoampoules, lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the formula I

in which R¹, R², R³, R⁴ each, independently of one another, denote H, A,Hal, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹²,S(O)_(n)R¹², NR¹⁰R¹¹, NO₂, CN, COOR¹⁰, CONR¹⁰R¹¹, NR¹⁰COR¹¹,NR¹⁰CONR¹⁰R¹¹, NR¹⁰SO_(n)R¹¹, COR¹⁰, SO₃H, SO_(n)NR¹⁰R¹¹, O-Alk-NR¹⁰R¹¹,O-Alk-O-Alk-NR¹⁰R¹¹, O-Alk-O—R¹², O[C(R¹²)₂]_(m)CONR¹⁰R¹¹,O-Alk-NR¹⁰COR¹¹, O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar,S(O)_(n)[C(R¹²)₂]_(m)Het or S(O)_(n)[C(R¹²)₂]_(m)Ar, D denotes

R⁵, R⁶, R⁷, R⁸ each, independently of one another, denote H, A,[C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het, [C(R¹²)₂]_(m)OCOA,[C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², S(O)_(n)R¹², NR¹⁰R¹¹, CN, COOR¹⁰,CONR¹⁰R¹¹, NR¹⁰COR¹¹, NR¹⁰CONR¹⁰R¹¹, NR¹⁰SO_(n)R¹¹, COR¹⁰, SO₃H,SO_(n)NR¹⁰R¹¹, O-Alk-NR¹⁰R¹¹, O[C(R¹²⁾ ₂]_(m)CONR¹⁰R¹¹, O-Alk-NR¹⁰COR¹¹,O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar, S(O)_(n)[C(R¹²)₂]_(m)Het orS(O)_(n)[C(R¹²)₂]_(m)Ar, R⁹ denotes H, A, S(O)_(n)[C(R¹²)₂]_(m)R¹⁰,CONR¹⁰R¹¹, COR¹⁰, SO_(n)NR¹⁰R¹¹, [C(R¹²)₂]_(m)Ar or [C(R¹²)₂]_(m)Het,R¹⁰, R¹¹ each, independently of one another, denote H, A, Ar or Het, Adenotes unbranched or branched alkyl having 1-10 C atoms, in which oneor two non-adjacent CH₂ groups may be replaced by O, S, SO, SO₂, NH,NA′, NAr, NHet and/or by —CH═CH— groups and/or in addition 1-7H atomsmay be replaced by F, Cl, Br, ═S, ═NR¹² and/or ═O or denotes cycloalkylhaving 3-7 C atoms, which is unsubstituted or mono-, di- ortrisubstituted by ═O, F, Cl, OH, OA′, OAr′, OHet′, SO_(n)A′, SO_(n)Ar′,SO_(n)Het′, NH₂, NHA′, NA′₂, NHAr′ and/or NHHet′, A′ denotes unbranchedor branched alkyl having 1-6 C atoms in which 1-7 H atoms may bereplaced by F and/or Cl, Alk denotes unbranched or branched alkylenehaving 1, 2, 3 or 4 C atoms, Ar denotes phenyl, naphthyl or biphenyl,each of which is unsubstituted or mono-, di-, tri-, tetra- orpentasubstituted by A, Hal, [C(R¹²)₂]_(m)Ar′, [C(R¹²)₂]_(m)Het′,O[C(R¹²)₂]_(m)R¹², S(O)_(n)R¹², NH₂, NHA′, NA′₂, NHAr′, NHHet′, NO₂, CN,COOR¹², CON(R¹²)₂, NR¹²COR¹², NR¹²CON(R¹²)₂, NR¹²SO_(n)R¹², COR¹², SO₃H,SO_(n)N(R¹²)₂, O-Alk-N(R¹²)₂, O[C(R¹²)₂]_(m)CON(R¹²)₂, O-Alk-NR¹²COR¹²,O[C(R¹²)₂]_(m)Het′, O[C(R¹²)₂]_(m)Ar′, S(O)_(n)[C(R¹²)₂]_(m)Het′ and/orS(O)_(n)[C(R¹²)₂]_(m)Ar′, Het denotes a mono- or bicyclic saturated,unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms,which may be mono-, di- or trisubstituted by Hal, A, [C(R¹² ₂]_(m)Ar′,[C(R¹²)₂]_(m)Het′, O[C(R¹² ₂]_(m)Art, O[C(R¹²)₂]_(m)Het′,[C(R¹²)₂]_(m)cycloalkyl, [C(R¹²)₂]_(m)OR¹², [C(R¹²)₂]_(m)N(R¹²)₂, NO₂,CN, [C(R¹²)₂]_(m)COOR¹², O[C(R¹²)₂]_(m)COOR¹², [C(R¹²)₂]_(m)CON(R¹²)₂,[C(R¹²)₂]_(m)CONR¹²N(R¹²)₂, O[C(R¹²)₂]_(m)CON(R¹²)₂,O[C(R¹²)₂]_(m)CONR¹²N(R¹²)₂, [C(R¹²)₂]_(m)NR¹²COA, NR¹²CON(R¹²)₂,[C(R¹²)₂]_(m)NR¹²SO₂A, COR¹², SO₂N(R¹²)₂, S(O)_(m)A, ═S, ═NR² and/or ═O(carbonyl oxygen), Ar′ denotes phenyl, naphthyl or biphenyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR¹²,N(R¹²)₂, NO₂, CN, COOR¹², CON(R¹²)₂, NR¹²COA, NR¹²CON(R¹²)₂, NR¹²SO₂A,COR¹², SO₂N(R¹²)₂, S(O)_(n)A, [C(R¹²)₂]_(m)COOR¹² and/orO[C(R¹²)₂]_(m)COOR¹², Het′ denotes a mono- or bicyclic saturated,unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms,which may be mono-, di- or trisubstituted by Hal, A, OR¹², N(R¹²)₂, NO₂,CN, COOR¹², CON(R¹²)₂, NR¹²COA, NR¹²SO₂A, COR¹², SO₂N(R¹²)₂, S(O)_(n)A,═S, ═NR¹² and/or ═O (carbonyl oxygen), R¹² denotes H or unbranched orbranched alkyl having 1, 2, 3, 4, 5 or 6 C atoms or denotes cycloalkylhaving 3-7 C atoms, unsubstituted or monosubstituted by ═O, Hal denotesF, Cl, Br or I, m denotes 0, 1, 2, 3 or 4, n denotes 0, 1 or 2, with theproviso that if D denotes thiazole then R¹ is not equal OCH₂Ar orOCH₂Het, and pharmaceutically usable salts and stereoisomers thereof,including mixtures thereof in all ratios.
 2. Compounds according toclaim 1 in which R¹, R², R³, R⁴ each, independently of one another,denote H, A, Hal, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het,[C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar,S(O)_(n)[C(R¹²)₂]_(m)Het, O-Alk-NR¹⁰R¹¹, O-Alk-O-Alk-NR¹⁰R¹¹,O-Alk-O—R¹² or S(O)_(n)[C(R¹²)₂]_(m)Ar, and pharmaceutically usablesalts and stereoisomers thereof, including mixtures thereof in allratios.
 3. Compounds according to claim 1 in which R¹ denotes H,O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar, O-Alk-NR¹⁰R¹¹, O-Alk-O-Alk-NR¹⁰R¹¹,O-Alk-O—R¹² or [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², and pharmaceuticallyusable salts and stereoisomers thereof, including mixtures thereof inall ratios.
 4. Compounds according to claim 1 in which R² denotes H, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 5. Compounds according to claim 1 inwhich R³ denotes Hal, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het,[C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar,S(O)_(n)[C(R¹²)₂]_(m)Het or S(O)_(n)[C(R¹²)₂]_(m)Ar, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 6. Compounds according to claim 1 inwhich R³ denotes Hal, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹²,O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar or S(O)_(n)[C(R¹²)₂]_(m)Ar, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 7. Compounds according to claim 1 inwhich R⁴ denotes H, and pharmaceutically usable salts and stereoisomersthereof, including mixtures thereof in all ratios.
 8. Compoundsaccording to claim 1 in which R⁵, R⁶, R⁷, R⁸ each, independently of oneanother, denote H, A, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het,[C(R¹²)₂]_(m)OCOA, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹² or COOR¹², andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 9. Compounds according to claim 1 inwhich R⁵ denotes H, and pharmaceutically usable salts and stereoisomersthereof, including mixtures thereof in all ratios.
 10. Compoundsaccording to claim 1 in which R⁶ denotes H, A, [C(R¹²)₂]_(m)Ar,[C(R¹²)₂]_(m)Het, [C(R¹²)₂]_(m)OCOA, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹² orCOOR¹², and pharmaceutically usable salts and stereoisomers thereof,including mixtures thereof in all ratios.
 11. Compounds according toclaim 1 in which R⁷ denotes H, and pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios. 12.Compounds according to claim 1 in which R⁸ denotes H, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 13. Compounds according to claim 1 inwhich R⁹ denotes H, A or [C(R¹²)₂]_(m)Het, and pharmaceutically usablesalts and stereoisomers thereof, including mixtures thereof in allratios.
 14. Compounds according to claim 1 in which R¹⁰, R¹¹ each,independently of one another, denote H or A, and pharmaceutically usablesalts and stereoisomers thereof, including mixtures thereof in allratios.
 15. Compounds according to claim 1 in which A denotes unbranchedor branched alkyl having 1-10 C atoms, in which one or two non-adjacentCH₂ groups may be replaced by O, S and/or NH and/or in addition 1-7Hatoms may be replaced by F, Cl and/or Br, or denotes cycloalkyl having3-7 C atoms, which is unsubstituted or monosubstituted by ═O, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 16. Compounds according to claim 1 inwhich Ar denotes phenyl, which is unsubstituted or monosubstituted byO[C(R¹²)₂]_(m)R¹², S(O)_(n)R¹² or SO_(n)N(R¹²)₂, and pharmaceuticallyusable salts and stereoisomers thereof, including mixtures thereof inall ratios.
 17. Compounds according to claim 1 in which Het denotes amonocyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or mono- ordisubstituted by A, [C(R¹²)₂]_(m)CON(R¹²)₂ and/or ═O (carbonyl oxygen),and pharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 18. Compounds according to claim 1 inwhich Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyridyl,pyrimidinyl, pyrazolyl, thiazolyl, pyrrolidinyl, piperidinyl,morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl orpiperazinyl, each of which is unsubstituted or mono- or disubstituted byA, [C(R¹²)₂]_(m)CON(R¹²)₂ and/or ═O (carbonyl oxygen), andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 19. Compounds according to claim 1 inwhich R¹, R², R³, R⁴ each, independently of one another, denote H, A,Hal, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹²,O-Alk-NR¹⁰R¹¹, O-Alk-O-Alk-NR¹⁰R¹¹, O-Alk-O—R¹², O[C(R¹²)₂]_(m)Het,O[C(R¹²)₂]_(m)Ar, S(O)_(n)[C(R¹²)₂]_(m)Het or S(O)_(n)[C(R¹²)₂]_(m)Ar, Ddenotes

R⁵, R⁶, R⁷, R⁸ each, independently of one another, denote H, A,[C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het, [C(R¹²)₂]_(m)OCOA,[C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹² or COOR¹², R⁹ denotes H, A or[C(R¹²)₂]_(m)Het, R¹⁰, R¹¹ each, independently of one another, denote Hor A, A denotes unbranched or branched alkyl having 1-10 C atoms, inwhich one or two non-adjacent CH₂ groups may be replaced by O, S and/orNH and/or in addition 1-7H atoms may be replaced by F, Cl and/or Br, ordenotes cycloalkyl having 3-7 C atoms, which is unsubstituted ormonosubstituted by ═O, Alk denotes unbranched or branched alkylenehaving 1, 2, 3 or 4 C atoms, Ar denotes phenyl, which is unsubstitutedor monosubstituted by O[C(R¹²)₂]_(m)R¹², S(O)_(n)R¹² or SO_(n)N(R¹²)₂,Het denotes a monocyclic saturated, unsaturated or aromatic heterocyclehaving 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-or disubstituted by A, [C(R¹²)₂]_(m)CON(R¹²)₂ and/or ═O (carbonyloxygen), R¹² denotes H or unbranched or branched alkyl having 1, 2, 3,4, 5 or 6 C atoms or denotes cycloalkyl having 3-7 C atoms,unsubstituted or monosubstituted by ═O, Hal denotes F, Cl, Br or I, mdenotes 0, 1, 2, 3 or 4, n denotes 0, 1 or 2, with the proviso that if Ddenotes thiazole then R¹ is not equal OCH₂Ar or OCH₂Het, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 20. Compounds according to claim 1 inwhich R¹ denotes H, O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar, O-Alk-NR¹⁰R¹¹,O-Alk-O-Alk-NR¹⁰R¹¹, O-Alk-O—R¹² or [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², R²denotes H, R³ denotes Hal, [C(R¹²)₂]_(m)Ar,[C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹², O[C(R¹²)₂]_(m)Het, O[C(R¹²)₂]_(m)Ar orS(O)_(n)[C(R¹²)₂]_(m)Ar, R⁴ denotes H, D denotes

R⁵ denotes H, R⁶ denotes H, A, [C(R¹²)₂]_(m)Ar, [C(R¹²)₂]_(m)Het,[C(R¹²)₂]_(m)OCOA, [C(R¹²)₂]_(m)O[C(R¹²)₂]_(m)R¹² or COOR¹², R⁷ denotesH, R⁸ denotes H, R⁹ denotes H, A or [C(R¹²)₂]_(m)Het, R¹⁰, R¹¹ each,independently of one another, denote H or A, A denotes unbranched orbranched alkyl having 1-10 C atoms, in which one or two non-adjacent CH₂groups may be replaced by O, S and/or NH and/or in addition 1-7H atomsmay be replaced by F, Cl and/or Br, or denotes cycloalkyl having 3-7 Catoms, which is unsubstituted or monosubstituted by ═O, Alk denotesunbranched or branched alkylene having 1, 2, 3 or 4 C atoms, Ar denotesphenyl, which is unsubstituted or monosubstituted by O[C(R¹²)₂]_(m)R¹²,S(O)_(n)R¹² or SO_(n)N(R¹²)₂, Het denotes a monocyclic saturated,unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms,which may be unsubstituted or mono- or disubstituted by A,[C(R¹²)₂]_(m)CON(R¹²)₂ and/or ═O (carbonyl oxygen), R¹² denotes H orunbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 C atoms ordenotes cycloalkyl having 3-7 C atoms, unsubstituted or monosubstitutedby ═O, Hal denotes F, Cl, Br or I, m denotes 0, 1, 2, 3 or 4, n denotes0, 1 or 2, with the proviso that if D denotes thiazole then R¹ is notequal OCH₂Ar or OCH₂Het, and pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios. 21.Compounds according to claim 1 in which R¹² denotes H, andpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 22. Compounds according to claim 1selected from the group no. name and/or structure “A1”(5-bromo-pyridine-2-yl)-(4-methyl-thiazole-2-yl)-amine “A2”(4-bromomethyl-thiazole-2-yl)-(5-bromo-pyridine-2-yl)- amine “A3”(5-bromo-pyridine-2-yl)-(4-imidazole-1-ylmethyl-thiazole-2- yl)-amine“A4” 2-(5-bromo-pyridine-2-ylamino)-thiazole-4-carboxylic acid ethylester “A5” acetic acid 2-(5-bromo-pyridine-2-yl amino)-thiazole-4-ylmethyl ester “A6”[2-(5-bromo-pyridine-2-ylamino)-thiazole-4-yl]-methanol “A7”[4-(2-amino-ethylsulfanylmethyl)-thiazole-2-yl]-(5-bromo-pyridine-2-yl)-amine “A8” (5-phenoxy-pyridine-2-yl)-thiazole-2-yl-amine“A9” acetic acid 2-(5-phenoxy-pyridine-2-ylamino)-thiazole-4- ylmethylester “A10” [2-(5-phenoxy-pyridine-2-ylamino)-thiazole-4-yl]-methanol“A11” (5-benzyloxy-pyridin-2-yl)-(1-methyl-1H-pyrazole-3-yl)- amine“A12” (5-phenylsulfanyl-pyridine-2-yl)-thiazole-2-yl-amine “A13”(5-phenylsulfinyl-pyridine-2-yl)-thiazole-2-yl-amine “A14”(5-phenylsulfonyl-pyridine-2-yl)-thiazole-2-yl-amine “A20”

“A21”

“A22”

“A23”

“A24”

“A25” (5-cyclopentyloxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)-amine “A26” (5-isobutoxy-pyridine-2-yl)-(1-methyl-1H-pyrazole-3-yl)-amine “A27” [5-(4-methanesulfonyl-phenoxy)-pyridine-2-yl]-(1-methyl-1H-pyrazol-3-yl)-amine “A28”[3-(2-methoxy-1-methyl-ethoxy)-5-phenoxy-pyridine-2-yl]-thiazole-2-yl-amine “A28a”[3-((R)-2-methoxy-1-methyl-ethoxy)-5-phenoxy-pyridin-2-yl]-thiazol-2-yl-amine “A28b”[3-((S)-2-methoxy-1-methyl-ethoxy)-5-phenoxy-pyridin-2-yl]-thiazol-2-yl-amine “A29”(3-cyclopentylmethoxy-5-phenoxy-pyridine-2-yl)-thiazole-2- yl-amine“A30” (5-benzyloxy-pyridine-2-yl)-thiazole-2-yl-amine “A31”[3-(2-methoxy-ethoxy)-5-(pyridine-3-yl-yloxy)-pyridine-2-yl]-thiazole-2-yl-amine “A32”[5-(4-methanesulfonyl-phenoxy)-3-(2-methoxy-ethoxy)-pyridine-2-yl]-thiazole-2-yl-amine “A90”

“A91”

“A92”

“A93”

“A94”

“A95”

“A96”

“A97”

“A98”

and pharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios.
 23. Process for the preparation ofcompounds of the formula I according to claim 1 and pharmaceuticallyusable salts and stereoisomers thereof, a) wherein D denotes

characterised in that a compound of the formula II

in which R¹, R², R³ and R⁴ have the meanings indicated in claim 1, isreacted with a compound of the formula III

in which L denotes Cl, Br, I or a free or reactively functionallymodified OH group and R⁵ and R⁶ have the meanings indicated in claim 1,or b) wherein D denotes

characterised in that a compound of the formula IV

in which R¹, R², R³, R⁴ and Hal have the meanings indicated in claims 1,is reacted with a compound of the formula VD-NH₂  V

in which D denotes and R⁷, R⁸ and R⁹ have the meanings indicated inclaim 1, or c) in a compound of the formula I, a radical R⁶ is convertedinto another radical R⁶ by i) converting a halogen group to an aromaticheterocycle; ii) converting an ester to an alcohol group and/or a baseor acid of the formula I is converted into one of its salts. 24.Medicaments comprising at least one compound according to claim 1 and/orpharmaceutically usable salts and stereoisomers thereof, includingmixtures thereof in all ratios, and optionally excipients and/oradjuvants.
 25. A method for the treatment of a disease or conditionresulting from underactivity of glucokinase or which can be treated byactivating glucokinase, comprising administering to a patient a compoundaccording to claims
 1. 26. A method according to claim 25, where thedisease or condition is insulin-dependent diabetes mellitus,non-insulin-dependent diabetes mellitus, obesity, neuropathy and/ornephropathy.
 27. Medicaments comprising at least one compound accordingto claim 1 and/or pharmaceutically usable salts and stereoisomersthereof, including mixtures thereof in all ratios, and at least onefurther medicament active ingredient.
 28. Set (kit) consisting ofseparate packs of (a) an effective amount of a compound according toclaim 1 and/or pharmaceutically usable salts and stereoisomers thereof,including mixtures thereof in all ratios, and (b) an effective amount ofa further medicament active ingredient.